Litchfield, K.
Reading, J.L.
Puttick, C.
Thakkar, K.
Abbosh, C.
Bentham, R.
Watkins, T.B.
Rosenthal, R.
Biswas, D.
Rowan, A.
Lim, E.
Al Bakir, M.
Turati, V.
Guerra-Assunção, J.A.
Conde, L.
Furness, A.J.
Saini, S.K.
Hadrup, S.R.
Herrero, J.
Lee, S.-.
Van Loo, P.
Enver, T.
Larkin, J.
Hellmann, M.D.
Turajlic, S.
Quezada, S.A.
McGranahan, N.
Swanton, C.
(2021). Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell,
Vol.184
(3),
pp. 596-614.e14.
Edwards, C.L.
Comito, F.
Agraso Busto, S.
Harland, C.
Turajlic, S.
Larkin, J.
Heelan, K.
Fearfield, L.
(2021). Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review The experience of a single large specialist institution. Clinical and experimental dermatology,
Vol.46
(2),
pp. 338-341.
Lee, C.-.
Motzer, R.J.
Glen, H.
Michaelson, M.D.
Larkin, J.
Minoshima, Y.
Kanekiyo, M.
Ikezawa, H.
Sachdev, P.
Dutcus, C.E.
Funahashi, Y.
Voss, M.H.
(2021). Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma. British journal of cancer,
Vol.124
(1),
pp. 237-246.
show abstract
Abstract
Background
No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.
Methods
Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3−5, CBS-low: 0–2; 2-factor-CBS high: 1–2, CBS-low: 0).
Results
PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).
Conclusions
The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.
Clinical trial registration
The clinical trial registration number is NCT01136733.
.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.M.
Meshcheryakov, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
van Akkooi, A.C.
Krepler, C.
Ibrahim, N.
Marreaud, S.
Kicinski, M.
Suciu, S.
Robert, C.
(2021). Reply to E Hindié. Journal of clinical oncology,
Vol.39
(8),
pp. 944-946.
McDermott, D.F.
Lee, J.-.
Bjarnason, G.A.
Larkin, J.M.
Gafanov, R.A.
Kochenderfer, M.D.
Jensen, N.V.
Donskov, F.
Malik, J.
Poprach, A.
Tykodi, S.S.
Alonso-Gordoa, T.
Cho, D.C.
Geertsen, P.F.
Climent Duran, M.A.
DiSimone, C.
Silverman, R.K.
Perini, R.F.
Schloss, C.
Atkins, M.B.
(2021). Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. Journal of clinical oncology,
Vol.39
(9),
pp. 1020-1028.
show abstract
PURPOSE Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types. .
Eisen, T.
Frangou, E.
Oza, B.
Ritchie, A.W.
Smith, B.
Kaplan, R.
Davis, I.D.
Stockler, M.R.
Albiges, L.
Escudier, B.
Larkin, J.
Bex, A.
Joniau, S.
Hancock, B.
Hermann, G.G.
Bellmunt, J.
Hodgkinson, E.
Stewart, G.D.
Barber, J.
Brown, J.
McMenemin, R.
Nathan, P.
Pickering, L.M.
Parmar, M.K.
Meade, A.
(2020). Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. Journal of clinical oncology,
Vol.38
(34),
pp. 4064-4075.
show abstract
PURPOSE SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART. .
Choueiri, T.K.
Motzer, R.J.
Rini, B.I.
Haanen, J.
Campbell, M.T.
Venugopal, B.
Kollmannsberger, C.
Gravis-Mescam, G.
Uemura, M.
Lee, J.L.
Grimm, M.-.
Gurney, H.
Schmidinger, M.
Larkin, J.
Atkins, M.B.
Pal, S.K.
Wang, J.
Mariani, M.
Krishnaswami, S.
Cislo, P.
Chudnovsky, A.
Fowst, C.
Huang, B.
di Pietro, A.
Albiges, L.
(2020). Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Annals of oncology,
Vol.31
(8),
pp. 1030-1039.
Owen, C.N.
Shoushtari, A.N.
Chauhan, D.
Palmieri, D.J.
Lee, B.
Rohaan, M.W.
Mangana, J.
Atkinson, V.
Zaman, F.
Young, A.
Hoeller, C.
Hersey, P.
Dummer, R.
Khattak, M.A.
Millward, M.
Patel, S.P.
Haydon, A.
Johnson, D.B.
Lo, S.
Blank, C.U.
Sandhu, S.
Carlino, M.S.
Larkin, J.M.
Menzies, A.M.
Long, G.V.
(2020). Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆. Annals of oncology,
Vol.31
(8),
pp. 1075-1082.
Sud, A.
Jones, M.E.
Broggio, J.
Loveday, C.
Torr, B.
Garrett, A.
Nicol, D.L.
Jhanji, S.
Boyce, S.A.
Gronthoud, F.
Ward, P.
Handy, J.M.
Yousaf, N.
Larkin, J.
Suh, Y.-.
Scott, S.
Pharoah, P.D.
Swanton, C.
Abbosh, C.
Williams, M.
Lyratzopoulos, G.
Houlston, R.
Turnbull, C.
(2020). Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic. Annals of oncology,
Vol.31
(8),
pp. 1065-1074.
Hall, P.E.
Shepherd, S.T.
Brown, J.
Larkin, J.
Jones, R.
Ralph, C.
Hawkins, R.
Chowdhury, S.
Boleti, E.
Bahl, A.
Fife, K.
Webb, A.
Crabb, S.J.
Geldart, T.
Hill, R.
Dunlop, J.
McLaren, D.
Ackerman, C.
Wimalasingham, A.
Beltran, L.
Nathan, P.
Powles, T.
(2020). Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy. European urology focus,
Vol.6
(5),
pp. 999-1005.
Khushalani, N.I.
Diab, A.
Ascierto, P.A.
Larkin, J.
Sandhu, S.
Sznol, M.
Koon, H.B.
Jarkowski, A.
Zhou, M.
Statkevich, P.
Geese, W.J.
Long, G.V.
(2020). Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. Future oncology,
Vol.16
(28),
pp. 2165-2175.
show abstract
Nivolumab, a PD-1 inhibitor, has demonstrated prolonged survival benefit in patients with advanced melanoma. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, provides sustained signaling through the IL-2βγ receptor, which activates effector T and natural killer cells. In the Phase I/II PIVOT-02 trial, the combination of bempegaldesleukin plus nivolumab was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. Here, we describe the design of and rationale for the Phase III, global, randomized, open-label PIVOT IO 001 trial comparing bempegaldesleukin plus nivolumab with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma. Primary end points include objective response rate, progression-free survival and overall survival. Key secondary end points include further investigation of safety/tolerability, previously assessed in the PIVOT-02 trial. Clinical Trial Registration: NCT03635983 ( ClinicalTrials.gov ) .
Comito, F.
Leslie, I.
Boos, L.
Furness, A.
Pickering, L.
Turajlic, S.
Larkin, J.
(2020). Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis. Journal of immunotherapy,
Vol.43
(8),
pp. 250-255.
Motzer, R.J.
Robbins, P.B.
Powles, T.
Albiges, L.
Haanen, J.B.
Larkin, J.
Mu, X.J.
Ching, K.A.
Uemura, M.
Pal, S.K.
Alekseev, B.
Gravis, G.
Campbell, M.T.
Penkov, K.
Lee, J.L.
Hariharan, S.
Wang, X.
Zhang, W.
Wang, J.
Chudnovsky, A.
di Pietro, A.
Donahue, A.C.
Choueiri, T.K.
(2020). Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nature medicine,
Vol.26
(11),
pp. 1733-1741.
Ascierto, P.A.
Del Vecchio, M.
Mandalá, M.
Gogas, H.
Arance, A.M.
Dalle, S.
Cowey, C.L.
Schenker, M.
Grob, J.-.
Chiarion-Sileni, V.
Márquez-Rodas, I.
Butler, M.O.
Maio, M.
Middleton, M.R.
de la Cruz-Merino, L.
Arenberger, P.
Atkinson, V.
Hill, A.
Fecher, L.A.
Millward, M.
Khushalani, N.I.
Queirolo, P.
Lobo, M.
de Pril, V.
Loffredo, J.
Larkin, J.
Weber, J.
(2020). Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. The lancet oncology,
Vol.21
(11),
pp. 1465-1477.
Ascierto, P.A.
Ribas, A.
Larkin, J.
McArthur, G.A.
Lewis, K.D.
Hauschild, A.
Flaherty, K.T.
McKenna, E.
Zhu, Q.
Mun, Y.
Dréno, B.
(2020). Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials. Journal of translational medicine,
Vol.18
(1).
show abstract
Abstract
Background
We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.
Methods
Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAFV600-mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause.
Results
RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3–16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8–2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.
Conclusion
A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment.
Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).
.
Litchfield, K.
Reading, J.L.
Lim, E.L.
Xu, H.
Liu, P.
Al-Bakir, M.
Wong, Y.N.
Rowan, A.
Funt, S.A.
Merghoub, T.
Perkins, D.
Lauss, M.
Svane, I.M.
Jönsson, G.
Herrero, J.
Larkin, J.
Quezada, S.A.
Hellmann, M.D.
Turajlic, S.
Swanton, C.
(2020). Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Nature communications,
Vol.11
(1).
Maio, M.
Hamid, O.
Larkin, J.
Covre, A.
Altomonte, M.
Calabrò, L.
Vardhana, S.A.
Robert, C.
Ibrahim, R.
Anichini, A.
Wolchok, J.D.
Giacomo, A.M.
(2020). Immune Checkpoint Inhibitors for Cancer Therapy in the COVID-19 Era. Clinical cancer research,
Vol.26
(16),
pp. 4201-4205.
Dummer, R.
Hauschild, A.
Santinami, M.
Atkinson, V.
Mandalà, M.
Kirkwood, J.M.
Chiarion Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Schachter, J.
Lesimple, T.
Plummer, R.
Dasgupta, K.
Gasal, E.
Tan, M.
Long, G.V.
Schadendorf, D.
(2020). Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. New england journal of medicine,
Vol.383
(12),
pp. 1139-1148.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.M.
Meshcheryakov, A.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
van Akkooi, A.C.
Krepler, C.
Ibrahim, N.
Marreaud, S.
Kicinski, M.
Suciu, S.
Robert, C.
(2020). Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. Journal of clinical oncology,
Vol.38
(33),
pp. 3925-3936.
show abstract
PURPOSE We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)–positive tumors. RESULTS Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1–positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups. .
Larkin, J.
Brown, M.P.
Arance, A.M.
Hauschild, A.
Queirolo, P.
Vecchio, M.D.
Ascierto, P.A.
Krajsová, I.
Schachter, J.
Neyns, B.
Garbe, C.
Sileni, V.C.
Mandalà, M.
Gogas, H.
Espinosa, E.
Hospers, G.
Lorigan, P.
Nyakas, M.
Guminski, A.
Liszkay, G.
Rutkowski, P.
Miller, W.
Donica, M.
Makrutzki, M.
Blank, C.
(2019). An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system. European journal of cancer,
Vol.107,
pp. 175-185.
Robert, C.
Flaherty, K.
Nathan, P.
Hersey, P.
Garbe, C.
Milhem, M.
Demidov, L.
Mohr, P.
Hassel, J.C.
Rutkowski, P.
Dummer, R.
Utikal, J.
Kiecker, F.
Larkin, J.
D'Amelio, A.
Mookerjee, B.
Schadendorf, D.
(2019). Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K–mutant advanced or metastatic melanoma. European journal of cancer,
Vol.109,
pp. 61-69.
Lewis, K.
Hauschild, A.
Larkin, J.
Ribas, A.
Flaherty, K.T.
McArthur, G.A.
Dréno, B.
McKenna, E.
Zhu, Q.
Mun, Y.
Ascierto, P.A.
(2019). Effect of concomitant dosing with acid-reducing agents and vemurafenib dose on survival in patients with BRAFV600 mutation–positive metastatic melanoma treated with vemurafenib ± cobimetinib. European journal of cancer,
Vol.116,
pp. 45-55.
Kreft, S.
Gesierich, A.
Eigentler, T.
Franklin, C.
Valpione, S.
Ugurel, S.
Utikal, J.
Haferkamp, S.
Blank, C.
Larkin, J.
Garbe, C.
Schadendorf, D.
Lorigan, P.
Schilling, B.
(2019). Efficacy of PD-1–based immunotherapy after radiologic progression on targeted therapy in stage IV melanoma. European journal of cancer,
Vol.116,
pp. 207-215.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.G.
Dalle, S.
Haydon, A.
Lichinitser, M.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A.M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.C.
Lupinacci, R.
Krepler, C.
Ibrahim, N.
Kicinski, M.
Marreaud, S.
van Akkooi, A.C.
Suciu, S.
Robert, C.
(2019). Prognostic and predictive value of AJCC-8 staging in the phase III EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma. European journal of cancer,
Vol.116,
pp. 148-157.
Mason, R.
Au, L.
Ingles Garces, A.
Larkin, J.
(2019). Current and emerging systemic therapies for cutaneous metastatic melanoma. Expert opinion on pharmacotherapy,
Vol.20
(9),
pp. 1135-1152.
Long, G.V.
Dummer, R.
Schadendorf, D.
Santinami, M.
Atkinson, V.
Mandalà, M.
Chiarion-Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Schachter, J.
Lesimple, T.
Plummer, R.
Dasgupta, K.
Haas, T.
Shilkrut, M.
Gasal, E.
Kefford, R.
Kirkwood, J.M.
Hauschild, A.
(2019). Reply to E Hindié and K R Hess. Journal of clinical oncology,
Vol.37
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pp. 1356-1358.
Motzer, R.J.
Penkov, K.
Haanen, J.
Rini, B.
Albiges, L.
Campbell, M.T.
Venugopal, B.
Kollmannsberger, C.
Negrier, S.
Uemura, M.
Lee, J.L.
Vasiliev, A.
Miller, W.H.
Gurney, H.
Schmidinger, M.
Larkin, J.
Atkins, M.B.
Bedke, J.
Alekseev, B.
Wang, J.
Mariani, M.
Robbins, P.B.
Chudnovsky, A.
Fowst, C.
Hariharan, S.
Huang, B.
di Pietro, A.
Choueiri, T.K.
(2019). Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New england journal of medicine,
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Larkin, J.
Minor, D.
D'Angelo, S.
Neyns, B.
Smylie, M.
Miller, W.H.
Gutzmer, R.
Linette, G.
Chmielowski, B.
Lao, C.D.
Lorigan, P.
Grossmann, K.
Hassel, J.C.
Sznol, M.
Daud, A.
Sosman, J.
Khushalani, N.
Schadendorf, D.
Hoeller, C.
Walker, D.
Kong, G.
Horak, C.
Weber, J.
(2018). Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. Journal of clinical oncology,
Vol.36
(4),
pp. 383-390.
show abstract
Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator’s choice chemotherapy (ICC; dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks). Patients were treated until they experienced progression or unacceptable toxicity, with follow-up of approximately 2 years. Results Two hundred seventy-two patients were randomly assigned to nivolumab (99% treated) and 133 to ICC (77% treated). More nivolumab-treated patients had brain metastases (20% v 14%) and increased lactate dehydrogenase levels (52% v 38%) at baseline; 41% of patients treated with ICC versus 11% of patients treated with nivolumab received anti–programmed death 1 agents after randomly assigned therapy. Median OS was 16 months for nivolumab versus 14 months for ICC (hazard ratio, 0.95; 95.54% CI, 0.73 to 1.24); median progression-free survival was 3.1 months versus 3.7 months, respectively (hazard ratio, 1.0; 95.1% CI, 0.78 to 1.436). Overall response rate (27% v 10%) and median duration of response (32 months v 13 months) were notably higher for nivolumab versus ICC. Fewer grade 3 and 4 treatment-related adverse events were observed in patients on nivolumab (14% v 34%). Conclusion Nivolumab demonstrated higher, more durable responses but no difference in survival compared with ICC. OS should be interpreted with caution as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the ICC group, and by an increased proportion of patients in the nivolumab group with poor prognostic factors. .
Flynn, M.
Pickering, L.
Larkin, J.
Turajlic, S.
(2018). Immune-checkpoint inhibitors in melanoma and kidney cancer: from sequencing to rational selection. Therapeutic advances in medical oncology,
Vol.10,
pp. 175883591877742-175883591877742.
show abstract
Immune-checkpoint inhibitors (ICPIs), including antibodies against cytotoxic T-lymphocyte associated antigen 4 and programmed cell death protein 1, have been shown to induce durable complete responses in a proportion of patients in the first-line and refractory setting in advanced melanoma and renal cell carcinoma. In fact, there are several lines of both targeted agents and ICPI that are now feasible treatment options. However, survival in the metastatic setting continues to be poor and there remains a need for improved therapeutic approaches. In order to enhance patient selection for the most appropriate next line of therapy, better predictive biomarkers of responsiveness will need to be developed in tandem with technologies to identify mechanisms of ICPI resistance. Adaptive, biomarker-driven trials will drive this evolution. The combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology (IO) drugs in order to circumvent ICPI resistance and enhance efficacy is discussed. Recent data support the role for both targeted therapies and ICPI in the adjuvant setting of melanoma and targeted therapies in the adjuvant setting for renal cell carcinoma, which may influence the consideration of treatment on subsequent relapse. Approaches to select the optimal treatment sequences for these patients will need to be refined. .
Hauschild, A.
Larkin, J.
Ribas, A.
Dréno, B.
Flaherty, K.T.
Ascierto, P.A.
Lewis, K.D.
McKenna, E.
Zhu, Q.
Mun, Y.
McArthur, G.A.
(2018). Modeled Prognostic Subgroups for Survival and Treatment Outcomes in BRAF V600–Mutated Metastatic Melanoma. Jama oncology,
Vol.4
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pp. 1382-1382.
Smith, H.G.
Joshi, K.
Strauss, D.C.
Hayes, A.J.
Larkin, J.
Smith, M.J.
(2018). The Impact of Effective Systemic Therapies on Surgery for Stage IV Metastatic Melanoma. Annals of surgical oncology,
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pp. S41-S41.
Grob, J.J.
Schadendorf, D.
Lorigan, P.
Ascierto, P.
Larkin, J.
Nathan, P.
Robert, C.
Hauschild, A.
Weber, J.
Daud, A.
Hamid, O.
Dummer, R.
Hansson, J.
Hoeller, C.
Schachter, J.
Van Akkooi, A.C.
Garbe, C.
(2018). Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III. European journal of cancer,
Vol.91,
pp. 168-170.
Valpione, S.
Carlino, M.S.
Mangana, J.
Mooradian, M.J.
McArthur, G.
Schadendorf, D.
Hauschild, A.
Menzies, A.M.
Arance, A.
Ascierto, P.A.
Di Giacomo, A.
de Rosa, F.
Larkin, J.
Park, J.J.
Goldinger, S.M.
Sullivan, R.J.
Xu, W.
Livingstone, E.
Weichenthal, M.
Rai, R.
Gaba, L.
Long, G.V.
Lorigan, P.
(2018). Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. European journal of cancer,
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Dréno, B.
Ascierto, P.A.
Atkinson, V.
Liszkay, G.
Maio, M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Dutriaux, C.
Garbe, C.
Bartley, K.
Karagiannis, T.
Chang, I.
Rooney, I.
Koralek, D.O.
Larkin, J.
McArthur, G.A.
Ribas, A.
(2018). Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation–positive melanoma. British journal of cancer,
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pp. 777-784.
Hayes, A.J.
Larkin, J.
(2018). BMI and outcomes in melanoma: more evidence for the obesity paradox. The lancet oncology,
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Yip, K.
Melcher, A.
Harrington, K.
Illidge, T.
Nobes, J.
Webster, A.
Smith, D.
Lorigan, P.
Nathan, P.
Larkin, J.
(2018). Pembrolizumab in Combination with Radiotherapy for Metastatic Melanoma — Introducing the PERM Trial. Clinical oncology,
Vol.30
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pp. 201-203.
Choueiri, T.K.
Larkin, J.
Oya, M.
Thistlethwaite, F.
Martignoni, M.
Nathan, P.
Powles, T.
McDermott, D.
Robbins, P.B.
Chism, D.D.
Cho, D.
Atkins, M.B.
Gordon, M.S.
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Tomita, Y.
Compagnoni, A.
Fowst, C.
di Pietro, A.
Rini, B.I.
(2018). Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. The lancet oncology,
Vol.19
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pp. 451-460.
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Furness, A.J.
Litchfield, K.
Joshi, K.
Rosenthal, R.
Ghorani, E.
Solomon, I.
Lesko, M.H.
Ruef, N.
Roddie, C.
Henry, J.Y.
Spain, L.
Ben Aissa, A.
Georgiou, A.
Wong, Y.N.
Smith, M.
Strauss, D.
Hayes, A.
Nicol, D.
O'Brien, T.
Mårtensson, L.
Ljungars, A.
Teige, I.
Frendéus, B.
Pule, M.
Marafioti, T.
Gore, M.
Larkin, J.
Turajlic, S.
Swanton, C.
Peggs, K.S.
Quezada, S.A.
Harrington, K.
Melcher, A.
Wotherspoon, A.
Francis, N.
Challacombe, B.
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Hazell, S.
Chandra, A.
Pickering, L.
Lynch, J.
Rudman, S.
Chowdhury, S.
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Varia, M.
Horsfield, C.
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Drake, W.
Hill, P.
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Mayer, E.
Olsburgh, J.
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Lester, J.
Morgan, F.
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Watkins, T.B.
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Pickering, L.
Schwarz, R.F.
Silva, B.
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Rosenthal, R.
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Wilson, G.A.
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(2018). Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell,
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Larkin, J.
Horswell, S.
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Au, L.
Jamal-Hanjani, M.
Challacombe, B.
Chandra, A.
Hazell, S.
Eichler-Jonsson, C.
Soultati, A.
Chowdhury, S.
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Lynch, J.
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Stamp, G.
Nye, E.
Jabbar, F.
Spain, L.
Lall, S.
Guarch, R.
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Proctor, I.
Pickering, L.
Gore, M.
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Stewart, A.
DiNatale, R.
Becerra, M.F.
Reznik, E.
Hsieh, J.J.
Richmond, T.A.
Mayhew, G.F.
Hill, S.M.
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Jones, C.
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Farmery, J.H.
O’Brien, T.
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Tarpey, P.
Angelopoulos, N.
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Butler, A.P.
Raine, K.
Stewart, G.D.
Challacombe, B.
Fernando, A.
Lopez, J.I.
Hazell, S.
Chandra, A.
Chowdhury, S.
Rudman, S.
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Stamp, G.
Fotiadis, N.
Pickering, L.
Au, L.
Spain, L.
Lynch, J.
Stares, M.
Teague, J.
Maura, F.
Wedge, D.C.
Horswell, S.
Chambers, T.
Litchfield, K.
Xu, H.
Stewart, A.
Elaidi, R.
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Csabai, I.
Gore, M.
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Larkin, J.
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Szallasi, Z.
Swanton, C.
Campbell, P.J.
(2018). Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal. Cell,
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Wongchenko, M.J.
Ribas, A.
Dréno, B.
Ascierto, P.A.
McArthur, G.A.
Gallo, J.D.
Rooney, I.A.
Hsu, J.
Koeppen, H.
Yan, Y.
Larkin, J.
(2018). Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF
mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib. Pigment cell & melanoma research,
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pp. 516-522.
Eggermont, A.M.
Blank, C.U.
Mandala, M.
Long, G.V.
Atkinson, V.
Dalle, S.
Haydon, A.
Lichinitser, M.
Khattak, A.
Carlino, M.S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P.A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Maio, M.
van den Eertwegh, A.J.
Grob, J.-.
Gutzmer, R.
Jamal, R.
Lorigan, P.
Ibrahim, N.
Marreaud, S.
van Akkooi, A.C.
Suciu, S.
Robert, C.
(2018). Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. New england journal of medicine,
Vol.378
(19),
pp. 1789-1801.
Hauschild, A.
Dummer, R.
Schadendorf, D.
Santinami, M.
Atkinson, V.
Mandalà, M.
Chiarion-Sileni, V.
Larkin, J.
Nyakas, M.
Dutriaux, C.
Haydon, A.
Robert, C.
Mortier, L.
Schachter, J.
Lesimple, T.
Plummer, R.
Dasgupta, K.
Haas, T.
Shilkrut, M.
Gasal, E.
Kefford, R.
Kirkwood, J.M.
Long, G.V.
(2018). Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600–Mutant Stage III Melanoma. Journal of clinical oncology,
Vol.36
(35),
pp. 3441-3449.
show abstract
Purpose Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600–mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term. Methods In this phase III trial, patients with resected BRAF V600–mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis–free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model. Results At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis–free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration. Conclusion Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors. .
Sun, M.
Marconi, L.
Eisen, T.
Escudier, B.
Giles, R.H.
Haas, N.B.
Harshman, L.C.
Quinn, D.I.
Larkin, J.
Pal, S.K.
Powles, T.
Ryan, C.W.
Sternberg, C.N.
Uzzo, R.
Choueiri, T.K.
Bex, A.
(2018). Adjuvant Vascular Endothelial Growth Factor–targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis. European urology,
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pp. 611-620.
Smith, M.J.
Smith, H.G.
Joshi, K.
Gore, M.
Strauss, D.C.
Hayes, A.J.
Larkin, J.
(2018). The impact of effective systemic therapies on surgery for stage IV melanoma. European journal of cancer,
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Hodi, F.S.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Rutkowski, P.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Wagstaff, J.
Dummer, R.
Ferrucci, P.F.
Smylie, M.
Hill, A.
Hogg, D.
Marquez-Rodas, I.
Jiang, J.
Rizzo, J.
Larkin, J.
Wolchok, J.D.
(2018). Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. The lancet oncology,
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pp. 1480-1492.
Wongchenko, M.J.
Ribas, A.
Ascierto, P.A.
Dréno, B.
Maria di Giacomo, A.
Garbe, C.
Chang, I.
Hsu, J.
Rooney, I.
Lu, W.
Koeppen, H.
Larkin, J.
Yan, Y.
McArthur, G.A.
(2018). Effects of Molecular Heterogeneity on Survival of Patients With BRAFV600-Mutated Melanoma Treated With Vemurafenib With or Without Cobimetinib in the coBRIM Study. Jco precision oncology,
(2),
pp. 1-18.
show abstract
Purpose The treatment of advanced BRAFV600-mutated melanomas with BRAF inhibitors (BRAFi) has improved survival, but the efficacy of BRAFi varies among individuals and the development of acquired resistance to BRAFi through reactivation of mitogen-activated protein kinase (MAPK) signaling is common. We performed an exploratory, retrospective analysis to investigate the effects of BRAFV600 allelic balance, coexisting oncogene mutations, cell proliferation signaling levels, and loss of PTEN expression on progression-free survival (PFS) in patients in the phase III coBRIM study, which compared the combination of the MEK inhibitor cobimetinib with the BRAFi vemurafenib versus vemurafenib as monotherapy. Methods Baseline tumor samples from the intention-to-treat population were analyzed by targeted deep sequencing at a median coverage of 3,600× and by immunohistochemistry for cell proliferation markers, BRAFV600E, and PTEN. The association of these biomarkers with PFS was assessed by Cox proportional hazards modeling. Gene expression in relation to loss of PTEN was profiled by RNA sequencing in 205 patient samples and 42 BRAFV600-mutated melanoma cell lines. Results Neither BRAFV600 allelic balance nor coexisting mutations in the RAS/RAF/RTK pathway affected PFS in either treatment group. Increased baseline MAPK signaling and cell proliferation did not affect PFS in patients treated with cobimetinib combined with vemurafenib. PTEN loss was associated with reduced PFS in patients treated with vemurafenib alone but not in patients treated with cobimetinib combined with vemurafenib. Conclusion Deeper inhibition of the MAPK pathway through targeting of both MEK and BRAF may override the effects of tumor heterogeneity and improve PFS in all patients with advanced BRAFV600 melanoma. .
Lu, W.
Burton, L.
Larkin, J.
Chapman, P.B.
Ascierto, P.A.
Ribas, A.
Robert, C.
Sosman, J.A.
McArthur, G.A.
Chang, I.
Caro, I.
Penuel, E.
Yan, Y.
Wongchenko, M.J.
(2018). Elevated Levels of BRAFV600 Mutant Circulating Tumor DNA and Circulating Hepatocyte Growth Factor Are Associated With Poor Prognosis in Patients With Metastatic Melanoma. Jco precision oncology,
(2),
pp. 1-17.
show abstract
Purpose We performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, BRAFV600 mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma. Materials and Methods This study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with BRAFV600 mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories. Results Patients with elevated levels of baseline BRAFV600 ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 v 21.4 months, respectively, and dacarbazine arm: 6.1 v 21.0 months, respectively). Median OS was also shorter in patients with high levels of cHGF compared with those with low cHGF (vemurafenib arm, 11.9 v 17.3 months, respectively, and dacarbazine arm, 6.1 v 14.4 months, respectively). In a multivariable proportional hazards model with adjustment for lactate dehydrogenase, Eastern Cooperative Oncology Group status, disease stage, and treatment, ctDNA and cHGF were both independent prognostic factors for OS, (HR, 1.75; 95% CI, 1.35 to 2.28 for high v undetectable ctDNA; HR, 1.24; 95% CI, 1.00 to 1.53 for high v low cHGF). Using partitioning analysis, we found that patients with elevated ctDNA combined with elevated cHGF constituted the highest risk group with significantly shorter OS. Conclusion Here, we report that BRIM-3 patients with high levels of ctDNA and cHGF have worse OS regardless of treatment and that these factors are independent prognostic markers for metastatic melanoma. .
Proskorovsky, I.
Benedict, A.
Negrier, S.
Bargo, D.
Sandin, R.
Ramaswamy, K.
Desai, J.
Cappelleri, J.C.
Larkin, J.
(2018). Axitinib, cabozantinib, or everolimus in the treatment of prior sunitinib-treated patients with metastatic renal cell carcinoma: results of matching-adjusted indirect comparison analyses. Bmc cancer,
Vol.18
(1).
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.J.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Dummer, R.
Smylie, M.
Rutkowski, P.
Ferrucci, P.F.
Hill, A.
Wagstaff, J.
Carlino, M.S.
Haanen, J.B.
Maio, M.
Marquez-Rodas, I.
McArthur, G.A.
Ascierto, P.A.
Long, G.V.
Callahan, M.K.
Postow, M.A.
Grossmann, K.
Sznol, M.
Dreno, B.
Bastholt, L.
Yang, A.
Rollin, L.M.
Horak, C.
Hodi, F.S.
Wolchok, J.D.
(2018). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma (vol 377, pg 1345, 2017). New england journal of medicine,
Vol.379
(22),
pp. 2185-2185.
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.J.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Dummer, R.
Smylie, M.
Rutkowski, P.
Ferrucci, P.F.
Hill, A.
Wagstaff, J.
Carlino, M.S.
Haanen, J.B.
Maio, M.
Marquez-Rodas, I.
McArthur, G.A.
Ascierto, P.A.
Long, G.V.
Callahan, M.K.
Postow, M.A.
Grossmann, K.
Sznol, M.
Dreno, B.
Bastholt, L.
Yang, A.
Rollin, L.M.
Horak, C.
Hodi, F.S.
Wolchok, J.D.
(2018). Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy (vol 375, pg 1845, 2016). New england journal of medicine,
Vol.379
(22),
pp. 2185-2185.
Lim, K.J.
Spain, L.
Barker, C.
Georgiou, A.
Walls, G.
Gore, M.
Turajlic, S.
Board, R.
Larkin, J.M.
Lorigan, P.
(2018). Contemporary outcomes from the use of regular imaging to detect relapse in high-risk cutaneous melanoma. Esmo open,
Vol.3
(2),
pp. e000317-e000317.
Spain, L.
Walls, G.
Messiou, C.
Turajlic, S.
Gore, M.
Larkin, J.
(2017). Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series. Cancer immunology, immunotherapy,
Vol.66
(1),
pp. 113-117.
Wongchenko, M.J.
McArthur, G.A.
Dréno, B.
Larkin, J.
Ascierto, P.A.
Sosman, J.
Andries, L.
Kockx, M.
Hurst, S.D.
Caro, I.
Rooney, I.
Hegde, P.S.
Molinero, L.
Yue, H.
Chang, I.
Amler, L.
Yan, Y.
Ribas, A.
(2017). Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib. Clinical cancer research,
Vol.23
(17),
pp. 5238-5245.
Long, G.V.
Weber, J.S.
Larkin, J.
Atkinson, V.
Grob, J.-.
Schadendorf, D.
Dummer, R.
Robert, C.
Márquez-Rodas, I.
McNeil, C.
Schmidt, H.
Briscoe, K.
Baurain, J.-.
Hodi, F.S.
Wolchok, J.D.
(2017). Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression. Jama oncology,
Vol.3
(11),
pp. 1511-1511.
Schadendorf, D.
Wolchok, J.D.
Hodi, F.S.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Chesney, J.
Robert, C.
Grossmann, K.
McDermott, D.
Walker, D.
Bhore, R.
Larkin, J.
Postow, M.A.
(2017). Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials. Journal of clinical oncology,
Vol.35
(34),
pp. 3807-3814.
show abstract
Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy. .
Chapman, P.B.
Robert, C.
Larkin, J.
Haanen, J.B.
Ribas, A.
Hogg, D.
Hamid, O.
Ascierto, P.A.
Testori, A.
Lorigan, P.C.
Dummer, R.
Sosman, J.A.
Flaherty, K.T.
Chang, I.
Coleman, S.
Caro, I.
Hauschild, A.
McArthur, G.A.
(2017). Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann oncol,
Vol.28
(10),
pp. 2581-2587.
show abstract
Background: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. Results: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. Conclusions: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. ClinicalTrials.gov: NCT01006980..
Weber, J.S.
Hodi, F.S.
Wolchok, J.D.
Topalian, S.L.
Schadendorf, D.
Larkin, J.
Sznol, M.
Long, G.V.
Li, H.
Waxman, I.M.
Jiang, J.
Robert, C.
(2017). Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. Journal of clinical oncology,
Vol.35
(7),
pp. 785-792.
show abstract
Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit. .
Spain, L.
Walls, G.
Julve, M.
O’Meara, K.
Schmid, T.
Kalaitzaki, E.
Turajlic, S.
Gore, M.
Rees, J.
Larkin, J.
(2017). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Annals of oncology,
Vol.28
(2),
pp. 377-385.
Grande, E.
Glen, H.
Aller, J.
Argenziano, G.
Lamas, M.J.
Ruszniewski, P.
Zamorano, J.L.
Edmonds, K.
Sarker, S.
Staehler, M.
Larkin, J.
(2017). Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma. Expert opinion on drug safety,
Vol.16
(12),
pp. 1413-1426.
O’reilly, A.
Larkin, J.
(2017). Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy. Expert review of anticancer therapy,
Vol.17
(7),
pp. 647-655.
O’Reilly, A.
Larkin, J.
(2017). The safety of nivolumab for the treatment of metastatic melanoma. Expert opinion on drug safety,
Vol.16
(8),
pp. 955-961.
Morganstein, D.L.
Lai, Z.
Spain, L.
Diem, S.
Levine, D.
Mace, C.
Gore, M.
Larkin, J.
(2017). Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clinical endocrinology,
Vol.86
(4),
pp. 614-620.
Spain, L.
Schmid, T.
Gore, M.
Larkin, J.
(2017). Efficacy of the combination of ipilimumab and nivolumab following progression on pembrolizumab in advanced melanoma with poor risk features. European journal of cancer,
Vol.75,
pp. 243-244.
Arce Vargas, F.
Furness, A.J.
Solomon, I.
Joshi, K.
Mekkaoui, L.
Lesko, M.H.
Miranda Rota, E.
Dahan, R.
Georgiou, A.
Sledzinska, A.
Ben Aissa, A.
Franz, D.
Werner Sunderland, M.
Wong, Y.N.
Henry, J.Y.
O’Brien, T.
Nicol, D.
Challacombe, B.
Beers, S.A.
Turajlic, S.
Gore, M.
Larkin, J.
Swanton, C.
Chester, K.A.
Pule, M.
Ravetch, J.V.
Marafioti, T.
Peggs, K.S.
Quezada, S.A.
Spain, L.
Wotherspoon, A.
Francis, N.
Smith, M.
Strauss, D.
Hayes, A.
Soultati, A.
Stares, M.
Spain, L.
Lynch, J.
Fotiadis, N.
Fernando, A.
Hazell, S.
Chandra, A.
Pickering, L.
Rudman, S.
Chowdhury, S.
Swanton, C.
Jamal-Hanjani, M.
Veeriah, S.
Shafi, S.
Czyzewska-Khan, J.
Johnson, D.
Laycock, J.
Bosshard-Carter, L.
Goh, G.
Rosenthal, R.
Gorman, P.
Murugaesu, N.
Hynds, R.E.
Wilson, G.
Birkbak, N.J.
Watkins, T.B.
McGranahan, N.
Horswell, S.
Mitter, R.
Escudero, M.
Stewart, A.
Van Loo, P.
Rowan, A.
Xu, H.
Turajlic, S.
Hiley, C.
Abbosh, C.
Goldman, J.
Stone, R.K.
Denner, T.
Matthews, N.
Elgar, G.
Ward, S.
Biggs, J.
Costa, M.
Begum, S.
Phillimore, B.
Chambers, T.
Nye, E.
Graca, S.
Al Bakir, M.
Hartley, J.A.
Lowe, H.L.
Herrero, J.
Lawrence, D.
Hayward, M.
Panagiotopoulos, N.
Kolvekar, S.
Falzon, M.
Borg, E.
Simeon, C.
Hector, G.
Smith, A.
Aranda, M.
Novelli, M.
Oukrif, D.
Janes, S.M.
Thakrar, R.
Forster, M.
Ahmad, T.
Lee, S.M.
Papadatos-Pastos, D.
Carnell, D.
Mendes, R.
George, J.
Navani, N.
Ahmed, A.
Taylor, M.
Choudhary, J.
Summers, Y.
Califano, R.
Taylor, P.
Shah, R.
Krysiak, P.
Rammohan, K.
Fontaine, E.
Booton, R.
Evison, M.
Crosbie, P.
Moss, S.
Idries, F.
Joseph, L.
Bishop, P.
Chaturved, A.
Quinn, A.M.
Doran, H.
Leek, A.
Harrison, P.
Moore, K.
Waddington, R.
Novasio, J.
Blackhall, F.
Rogan, J.
Smith, E.
Dive, C.
Tugwood, J.
Brady, G.
Rothwell, D.G.
Chemi, F.
Pierce, J.
Gulati, S.
Naidu, B.
Langman, G.
Trotter, S.
Bellamy, M.
Bancroft, H.
Kerr, A.
Kadiri, S.
Webb, J.
Middleton, G.
Djearaman, M.
Fennell, D.
Shaw, J.A.
Le Quesne, J.
Moore, D.
Nakas, A.
Rathinam, S.
Monteiro, W.
Marshall, H.
Nelson, L.
Bennett, J.
Riley, J.
Primrose, L.
Martinson, L.
Anand, G.
Khan, S.
Amadi, A.
Nicolson, M.
Kerr, K.
Palmer, S.
Remmen, H.
Miller, J.
Buchan, K.
Chetty, M.
Gomersall, L.
Lester, J.
Edwards, A.
Morgan, F.
Adams, H.
Davies, H.
Kornaszewska, M.
Attanoos, R.
Lock, S.
Verjee, A.
MacKenzie, M.
Wilcox, M.
Bell, H.
Iles, N.
Hackshaw, A.
Ngai, Y.
Smith, S.
Gower, N.
Ottensmeier, C.
Chee, S.
Johnson, B.
Alzetani, A.
Shaw, E.
Lim, E.
De Sousa, P.
Barbosa, M.T.
Bowman, A.
Jorda, S.
Rice, A.
Raubenheimer, H.
Proli, C.
Cufari, M.E.
Ronquillo, J.C.
Kwayie, A.
Bhayani, H.
Hamilton, M.
Bakar, Y.
Mensah, N.
Ambrose, L.
Devaraj, A.
Buderi, S.
Finch, J.
Azcarate, L.
Chavan, H.
Green, S.
Mashinga, H.
Nicholson, A.G.
Lau, K.
Sheaff, M.
Schmid, P.
Conibear, J.
Ezhil, V.
Ismail, B.
Irvin-sellers, M.
Prakash, V.
Russell, P.
Light, T.
Horey, T.
Danson, S.
Bury, J.
Edwards, J.
Hill, J.
Matthews, S.
Kitsanta, Y.
Suvarna, K.
Fisher, P.
Keerio, A.D.
Shackcloth, M.
Gosney, J.
Postmus, P.
Feeney, S.
Asante-Siaw, J.
(2017). Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity,
Vol.46
(4),
pp. 577-586.
Rothermundt, C.
von Rappard, J.
Eisen, T.
Escudier, B.
Grünwald, V.
Larkin, J.
McDermott, D.
Oldenburg, J.
Porta, C.
Rini, B.
Schmidinger, M.
Sternberg, C.N.
Putora, P.M.
(2017). Second-line treatment for metastatic clear cell renal cell cancer: experts’ consensus algorithms. World journal of urology,
Vol.35
(4),
pp. 641-648.
Bracarda, S.
Negrier, S.
Casper, J.
Porta, C.
Schmidinger, M.
Larkin, J.
Gross Goupil, M.
Escudier, B.
(2017). How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert review of anticancer therapy,
Vol.17
(3),
pp. 227-233.
Bowyer, S.
Prithviraj, P.
Lorigan, P.
Larkin, J.
McArthur, G.
Atkinson, V.
Millward, M.
Khou, M.
Diem, S.
Ramanujam, S.
Kong, B.
Liniker, E.
Guminski, A.
Parente, P.
Andrews, M.C.
Parakh, S.
Cebon, J.
Long, G.V.
Carlino, M.S.
Klein, O.
(2017). Reply to ‘Comment on ‘Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy’’. British journal of cancer,
Vol.116
(8),
pp. e15-e15.
Dreno, B.
Ribas, A.
Larkin, J.
Ascierto, P.A.
Hauschild, A.
Thomas, L.
Grob, J.-.
Koralek, D.O.
Rooney, I.
Hsu, J.J.
McKenna, E.F.
McArthur, G.A.
(2017). Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Annals of oncology,
Vol.28
(5),
pp. 1137-1144.
Wolchok, J.D.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Wagstaff, J.
Schadendorf, D.
Ferrucci, P.F.
Smylie, M.
Dummer, R.
Hill, A.
Hogg, D.
Haanen, J.
Carlino, M.S.
Bechter, O.
Maio, M.
Marquez-Rodas, I.
Guidoboni, M.
McArthur, G.
Lebbé, C.
Ascierto, P.A.
Long, G.V.
Cebon, J.
Sosman, J.
Postow, M.A.
Callahan, M.K.
Walker, D.
Rollin, L.
Bhore, R.
Hodi, F.S.
Larkin, J.
(2017). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New england journal of medicine,
Vol.377
(14),
pp. 1345-1356.
Larkin, J.
Chmielowski, B.
Lao, C.D.
Hodi, F.S.
Sharfman, W.
Weber, J.
Suijkerbuijk, K.P.
Azevedo, S.
Li, H.
Reshef, D.
Avila, A.
Reardon, D.A.
(2017). Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. The oncologist,
Vol.22
(6),
pp. 709-718.
Stewart, G.D.
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show abstract
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti–programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes. .
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(2016). Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. The lancet oncology,
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pp. 1317-1324.
Ascierto, P.A.
McArthur, G.A.
Dréno, B.
Atkinson, V.
Liszkay, G.
Di Giacomo, A.M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Dutriaux, C.
Garbe, C.
Yan, Y.
Wongchenko, M.
Chang, I.
Hsu, J.J.
Koralek, D.O.
Rooney, I.
Ribas, A.
Larkin, J.
(2016). Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The lancet oncology,
Vol.17
(9),
pp. 1248-1260.
Spain, L.
Goode, E.
McGovern, Y.
Joshi, K.
Larkin, J.
(2016). The combination of vemurafenib and cobimetinib in advanced melanoma. Expert opinion on orphan drugs,
Vol.4
(11),
pp. 1105-1111.
Turajlic, S.
Larkin, J.
(2016). Systemic treatment of advanced papillary renal cell carcinoma: Where next?. European journal of cancer,
Vol.69,
pp. 223-225.
Spain, L.
Walls, G.
Julve, M.
O'Meara, K.
Schmid, T.
Kalaitzaki, E.
Turajlic, S.
Gore, M.
Rees, J.
Larkin, J.
(2016). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann oncol,
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Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Wagstaff, J.
Hogg, D.
Hill, A.
Carlino, M.S.
Wolter, P.
Lebbe, C.
Schachter, J.
Thomas, L.
Hassel, J.C.
Lorigan, P.
Walker, D.
Jiang, J.
Hodi, F.S.
Wolchok, J.D.
(2016). Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients with advanced melanoma (MEL) (CheckMate 067). Oncology research and treatment,
Vol.39,
pp. 40-40.
Larkin, J.
Lao, C.D.
Urba, W.J.
McDermott, D.F.
Horak, C.
Jiang, J.
Wolchok, J.D.
(2015). Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma. Jama oncology,
Vol.1
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pp. 433-433.
Lorigan, P.
Ascierto, P.A.
Dummer, R.
Eggermont, A.M.
Flaherty, K.T.
Garbe, C.
Gogas, H.
Hauschild, A.
Kefford, R.F.
Kirkwood, J.M.
Larkin, J.
Long, G.V.
Maio, M.
McArthur, G.A.
Ribas, A.
Robert, C.
Schadendorf, D.
Sondak, V.K.
Wolchok, J.D.
Hudson, A.M.
(2015). Expanded access programmes: patient interests versus clinical trial integrity. Lancet oncology,
Vol.16
(1),
pp. 15-17.
Coupe, N.
Corrie, P.
Hategan, M.
Larkin, J.
Gore, M.
Gupta, A.
Wise, A.
Suter, S.
Ciria, C.
Love, S.
Collins, L.
Middleton, M.R.
(2015). PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. Eur j cancer,
Vol.51
(3),
pp. 359-366.
show abstract
BACKGROUND: We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation. METHODS: In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease. FINDINGS: 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached). INTERPRETATION: Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation..
Larkin, J.
Paine, A.
Foley, G.
Mitchell, S.
Chen, C.
(2015). First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis. Expert opinion on pharmacotherapy,
Vol.16
(13),
pp. 1915-1927.
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.J.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Dummer, R.
Smylie, M.
Rutkowski, P.
Ferrucci, P.F.
Hill, A.
Wagstaff, J.
Carlino, M.S.
Haanen, J.B.
Maio, M.
Marquez-Rodas, I.
McArthur, G.A.
Ascierto, P.A.
Long, G.V.
Callahan, M.K.
Postow, M.A.
Grossmann, K.
Sznol, M.
Dreno, B.
Bastholt, L.
Yang, A.
Rollin, L.M.
Horak, C.
Hodi, F.S.
Wolchok, J.D.
(2015). Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New england journal of medicine,
Vol.373
(1),
pp. 23-34.
Martin-Liberal, J.
Kordbacheh, T.
Larkin, J.
(2015). Safety of pembrolizumab for the treatment of melanoma. Expert opinion on drug safety,
Vol.14
(6),
pp. 957-964.
Sinha, R.
Larkin, J.
Fearfield, L.
(2015). Clinical resolution of vemurafenib-induced squamous cell carcinoma with topical 5-fluorouracil. British journal of dermatology,
Vol.172
(4),
pp. 1135-1136.
Hirata, E.
Girotti, M.R.
Viros, A.
Hooper, S.
Spencer-Dene, B.
Matsuda, M.
Larkin, J.
Marais, R.
Sahai, E.
(2015). Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling. Cancer cell,
Vol.27
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pp. 574-588.
Weber, J.S.
D'Angelo, S.P.
Minor, D.
Hodi, F.S.
Gutzmer, R.
Neyns, B.
Hoeller, C.
Khushalani, N.I.
Miller, W.H.
Lao, C.D.
Linette, G.P.
Thomas, L.
Lorigan, P.
Grossmann, K.F.
Hassel, J.C.
Maio, M.
Sznol, M.
Ascierto, P.A.
Mohr, P.
Chmielowski, B.
Bryce, A.
Svane, I.M.
Grob, J.-.
Krackhardt, A.M.
Horak, C.
Lambert, A.
Yang, A.S.
Larkin, J.
(2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The lancet oncology,
Vol.16
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pp. 375-384.
Kovac, M.
Navas, C.
Horswell, S.
Salm, M.
Bardella, C.
Rowan, A.
Stares, M.
Castro-Giner, F.
Fisher, R.
de Bruin, E.C.
Kovacova, M.
Gorman, M.
Makino, S.
Williams, J.
Jaeger, E.
Jones, A.
Howarth, K.
Larkin, J.
Pickering, L.
Gore, M.
Nicol, D.L.
Hazell, S.
Stamp, G.
O’Brien, T.
Challacombe, B.
Matthews, N.
Phillimore, B.
Begum, S.
Rabinowitz, A.
Varela, I.
Chandra, A.
Horsfield, C.
Polson, A.
Tran, M.
Bhatt, R.
Terracciano, L.
Eppenberger-Castori, S.
Protheroe, A.
Maher, E.
El Bahrawy, M.
Fleming, S.
Ratcliffe, P.
Heinimann, K.
Swanton, C.
Tomlinson, I.
(2015). Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nature communications,
Vol.6
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Thomas, C.L.
Mortimer, P.S.
Larkin, J.M.
Basu, T.N.
Gore, M.E.
Fearfield, L.
(2015). MEK-inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma: a case series. Australasian journal of dermatology,
Vol.56,
pp. 78-78.
Bex, A.
Larkin, J.
Voss, M.
(2015). Challenging the Treatment Paradigm for Advanced Renal Cell Carcinoma: A Review of Systemic and Localized Therapies. American society of clinical oncology educational book,
(35),
pp. e239-e247.
show abstract
The current standard of care for the management of advanced renal cell carcinoma (RCC) revolves around systemic therapy with molecularly targeted agents. Over the last decade, a total of seven targeted drugs have been approved but, altogether, only exploit two molecular targets in this disease: the vascular endothelial growth factor (VEGF) axis and the mammalian target of rapamycin (mTOR). Introduction of these agents has markedly improved outcomes compared with those in the cytokine era, yet comparatively little progress has been made since registration of the first targeted therapeutics occurred 10 years ago. In this article, we review efforts to improve on this current treatment paradigm. We discuss novel targets in this disease and corresponding new agents under investigation. The article dedicates particular attention to targeted immunotherapeutics, which are rapidly emerging as a new category of interest in this disease. Last, we review current data supporting the use of surgical interventions to improve outcomes in patients with metastatic disease. .
Motzer, R.J.
Escudier, B.
McDermott, D.F.
George, S.
Hammers, H.J.
Srinivas, S.
Tykodi, S.S.
Sosman, J.A.
Procopio, G.
Plimack, E.R.
Castellano, D.
Choueiri, T.K.
Gurney, H.
Donskov, F.
Bono, P.
Wagstaff, J.
Gauler, T.C.
Ueda, T.
Tomita, Y.
Schutz, F.A.
Kollmannsberger, C.
Larkin, J.
Ravaud, A.
Simon, J.S.
Xu, L.-.
Waxman, I.M.
Sharma, P.
(2015). Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New england journal of medicine,
Vol.373
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pp. 1803-1813.
Schadendorf, D.
Amonkar, M.M.
Stroyakovskiy, D.
Levchenko, E.
Gogas, H.
de Braud, F.
Grob, J.-.
Bondarenko, I.
Garbe, C.
Lebbe, C.
Larkin, J.
Chiarion-Sileni, V.
Millward, M.
Arance, A.
Mandalà, M.
Flaherty, K.T.
Nathan, P.
Ribas, A.
Robert, C.
Casey, M.
DeMarini, D.J.
Irani, J.G.
Aktan, G.
Long, G.V.
(2015). Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. European journal of cancer,
Vol.51
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pp. 833-840.
Yousaf, N.
Davidson, M.
Goode, E.
Thomas, C.
Hung, R.
Gore, M.
Larkin, J.
(2015). The cost of ipilimumab toxicity. Melanoma research,
Vol.25
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pp. 259-264.
Pickering, L.M.
Larkin, J.
(2015). Carbonic anhydrase IX in resected clear cell RCC. Nature reviews urology,
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pp. 309-310.
Martin-Liberal, J.
Furness, A.J.
Joshi, K.
Peggs, K.S.
Quezada, S.A.
Larkin, J.
(2015). Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer immunology, immunotherapy,
Vol.64
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pp. 765-767.
Gulati, S.
Turajlic, S.
Larkin, J.
Bates, P.A.
Swanton, C.
(2015). Relapse models for clear cell renal carcinoma. The lancet oncology,
Vol.16
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pp. e376-e378.
Long, G.V.
Stroyakovskiy, D.
Gogas, H.
Levchenko, E.
de Braud, F.
Larkin, J.
Garbe, C.
Jouary, T.
Hauschild, A.
Grob, J.-.
Chiarion-Sileni, V.
Lebbe, C.
Mandalà, M.
Millward, M.
Arance, A.
Bondarenko, I.
Haanen, J.B.
Hansson, J.
Utikal, J.
Ferraresi, V.
Kovalenko, N.
Mohr, P.
Probachai, V.
Schadendorf, D.
Nathan, P.
Robert, C.
Ribas, A.
DeMarini, D.J.
Irani, J.G.
Swann, S.
Legos, J.J.
Jin, F.
Mookerjee, B.
Flaherty, K.
(2015). Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The lancet,
Vol.386
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pp. 444-451.
Wolchok, J.D.
Chiarion-Sileni, V.
Gonzalez, R.
Rutkowski, P.
Grob, J.J.
Cowey, C.L.
Lao, C.D.
Schadendorf, D.
Ferrucci, P.F.
Smylie, M.
Dummer, R.
Hill, A.
Haanen, J.
Maio, M.
McArthur, G.
Yang, A.
Rollin, L.
Horak, C.
Larkin, J.
Hodi, F.S.
(2015). CHECKMATE 067: A PHASE III RANDOMIZED DOUBLE-BLIND STUDY OF NIVOLUMAB (NIVO) MONOTHERAPY OR NIVO COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI MONOTHERAPY IN PREVIOUSLY UNTREATED PATIENTS (PTS) WITH ADVANCED MELANOMA (MEL). Asia-pacific journal of clinical oncology,
Vol.11,
pp. 68-68.
Soultati, A.
Stares, M.
Swanton, C.
Larkin, J.
Turajlic, S.
(2015). How should clinicians address intratumour heterogeneity in clear cell renal cell carcinoma?. Current opinion in urology,
Vol.25
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pp. 358-366.
Rothermundt, C.
Bailey, A.
Cerbone, L.
Eisen, T.
Escudier, B.
Gillessen, S.
Grünwald, V.
Larkin, J.
McDermott, D.
Oldenburg, J.
Porta, C.
Rini, B.
Schmidinger, M.
Sternberg, C.
Putora, P.M.
(2015). Algorithms in the First‐Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma—Analysis Using Diagnostic Nodes. The oncologist,
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pp. 1028-1035.
Moriceau, G.
Hugo, W.
Hong, A.
Shi, H.
Kong, X.
Yu, C.C.
Koya, R.C.
Samatar, A.A.
Khanlou, N.
Braun, J.
Ruchalski, K.
Seifert, H.
Larkin, J.
Dahlman, K.B.
Johnson, D.B.
Algazi, A.
Sosman, J.A.
Ribas, A.
Lo, R.S.
(2015). Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer cell,
Vol.27
(2),
pp. 240-256.
show abstract
Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity. .
Sinha, R.
Larkin, J.
Gore, M.
Fearfield, L.
(2015). Cutaneous toxicities associated with vemurafenib therapy in 107 patients withBRAFV600E mutation-positive metastatic melanoma, including recognition and management of rare presentations. British journal of dermatology,
Vol.173
(4),
pp. 1024-1031.
Turajlic, S.
Larkin, J.
Swanton, C.
(2015). Academically led clinical trials: challenges and opportunities. Annals of oncology,
Vol.26
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pp. 2010-2011.
Motzer, R.
Hutson, T.
Glen, H.
Michaelson, M.D.
Molina, A.
Eisen, T.
Jassem, J.
Zolnierek, J.
Maroto, P.
Mellado, B.
Melichar, B.
Tomasek, J.
Kim, H.-.
Wood, K.
Dutcus, C.
Larkin, J.
(2015). Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LEN plus EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). Oncology research and treatment,
Vol.38,
pp. 203-204.
Ahmad, S.S.
Qian, W.
Ellis, S.
Mason, E.
Khattak, M.A.
Gupta, A.
Shaw, H.
Quinton, A.
Kovarikova, J.
Thillai, K.
Rao, A.
Board, R.
Nobes, J.
Dalgleish, A.
Grumett, S.
Maraveyas, A.
Danson, S.
Talbot, T.
Harries, M.
Marples, M.
Plummer, R.
Kumar, S.
Nathan, P.
Middleton, M.R.
Larkin, J.
Lorigan, P.
Wheater, M.
Ottensmeier, C.H.
Corrie, P.G.
(2015). Ipilimumab in the real world. Melanoma research,
Vol.25
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pp. 432-442.
Kanu, N.
Grönroos, E.
Martinez, P.
Burrell, R.A.
Yi Goh, X.
Bartkova, J.
Maya-Mendoza, A.
Mistrík, M.
Rowan, A.J.
Patel, H.
Rabinowitz, A.
East, P.
Wilson, G.
Santos, C.R.
McGranahan, N.
Gulati, S.
Gerlinger, M.
Birkbak, N.J.
Joshi, T.
Alexandrov, L.B.
Stratton, M.R.
Powles, T.
Matthews, N.
Bates, P.A.
Stewart, A.
Szallasi, Z.
Larkin, J.
Bartek, J.
Swanton, C.
(2015). SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene,
Vol.34
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pp. 5699-5708.
Wilkins, A.
Furness, A.
W Corbett, R.
Bloomfield, A.
Porta, N.
Morris, S.
Ali, Z.
Larkin, J.
Harrington, K.
(2015). The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. British journal of cancer,
Vol.113
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pp. 1275-1281.
Motzer, R.J.
Hutson, T.E.
Glen, H.
Michaelson, M.D.
Molina, A.
Eisen, T.
Jassem, J.
Zolnierek, J.
Maroto, J.P.
Mellado, B.
Melichar, B.
Tomasek, J.
Kremer, A.
Kim, H.-.
Wood, K.
Dutcus, C.
Larkin, J.
(2015). Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. The lancet oncology,
Vol.16
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pp. 1473-1482.
Larkin, J.
Chiarion-Sileni, V.
Gonzalez, R.
Grob, J.-.
Cowey, C.L.
Lao, C.D.
Wagstaff, J.
Hogg, D.
Hill, A.
Carlino, M.S.
Wolter, P.
Lebbe, C.
Schachter, J.
Thomas, L.
Hassal, J.C.
Lorigan, P.
Walker, D.
Jiang, J.
Hodi, F.S.
Wolchok, J.D.
(2015). EFFICACY AND SAFETY IN KEY PATIENT SUBGROUPS OF NIVOLUMAB (NIVO) ALONE OR COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI ALONE IN TREATMENT-NAIVE PATIENTS WITH ADVANCED MELANOMA (MEL) (CHECKMATE 067). Asia-pacific journal of clinical oncology,
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pp. 126-126.
Spain, L.
Younger, E.
Hatipoglu, E.
Larkin, J.
(2015). Pembrolizumab in the management of metastatic melanoma. Melanoma management,
Vol.2
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pp. 315-325.
Diem, S.
Kasenda, B.
Martin-Liberal, J.
Lee, A.
Chauhan, D.
Gore, M.
Larkin, J.
(2015). Prognostic score for patients with advanced melanoma treated with ipilimumab. European journal of cancer,
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pp. 2785-2791.
Turajlic, S.
Larkin, J.
Swanton, C.
(2015). SnapShot: Renal Cell Carcinoma. Cell,
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pp. 1556-1556.e1.
Gore, M.
Larkin, J.
(2015). Precision oncology: where next?. The lancet oncology,
Vol.16
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pp. 1593-1595.
Dummer, R.
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Larkin, J.
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Hauschild, A.
(2015). Integrating first-line treatment options into clinical practice. Melanoma research,
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pp. 461-469.
Richman, J.
Martin-Liberal, J.
Diem, S.
Larkin, J.
(2015). BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert opinion on pharmacotherapy,
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pp. 1285-1297.
Jamal-Hanjani, M.
Quezada, S.A.
Larkin, J.
Swanton, C.
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pp. 1258-1266.
Colomba, E.
Albiges, L.
Le Teuff, G.
Eisen, T.
Stewart, G.
Fife, K.
Srinivasan, A.
Larkin, J.M.
Biondo, A.
Pickering, L.M.
Boyle, H.J.
Derosa, L.
Ralph, C.
Saldana, C.
Bernhard, J.-.
Barthelemy, P.
Recine, F.
Escudier, B.
RCCG,
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(2015). Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New england journal of medicine,
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Robert, C.
Schachter, J.
Long, G.V.
Arance, A.
Grob, J.J.
Mortier, L.
Daud, A.
Carlino, M.S.
McNeil, C.
Lotem, M.
Larkin, J.
Lorigan, P.
Neyns, B.
Blank, C.U.
Hamid, O.
Mateus, C.
Shapira-Frommer, R.
Kosh, M.
Zhou, H.
Ibrahim, N.
Ebbinghaus, S.
Ribas, A.
(2015). Pembrolizumab versus Ipilimumab in Advanced Melanoma. New england journal of medicine,
Vol.372
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pp. 2521-2532.
Kasenda, B.
Larkin, J.
Gore, M.
(2015). Immunotherapies in Early and Advanced Renal Cell Cancer. ,
,
pp. 1-10.
Martin-Liberal, J.
Larkin, J.
(2015). Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Future oncol,
Vol.11
(4),
pp. 579-589.
show abstract
Vemurafenib was the first selective BRAF inhibitor licensed in cancer. It is indicated for the treatment of patients affected by advanced melanoma with BRAF V600 mutation. It has shown successful results in terms of efficacy together with a favorable toxicity profile. Other compounds such as the BRAF inhibitor dabrafenib and the immunotherapeutic agent ipilimumab are also approved in the same group of patients. This article reviews the chemistry, pharmacokinetics, pharmacodynamics and clinical development of vemurafenib. Moreover, its efficacy and toxicity are compared with dabrafenib and ipilimumab. A number of trials with vemurafenib alone or in combination with other drugs are also analyzed. These trials will determine the role of vemurafenib in the treatment of BRAF mutant melanoma in forthcoming years..
Molina, A.M.
Hutson, T.E.
Larkin, J.
Gold, A.M.
Wood, K.
Carter, D.
Motzer, R.
Michaelson, M.D.
(2014). A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer chemotherapy and pharmacology,
Vol.73
(1),
pp. 181-189.
Gerlinger, M.
Horswell, S.
Larkin, J.
Rowan, A.J.
Salm, M.P.
Varela, I.
Fisher, R.
McGranahan, N.
Matthews, N.
Santos, C.
Martinez, P.
Phillimore, B.
Begum, S.
Rabinowitz, A.
Spencer-Dene, B.
Gulati, S.
Bates, P.A.
Stamp, G.
Pickering, L.
Gore, M.
Nicol, D.L.
Hazell, S.
Futreal, P.A.
Stewart, A.
Swanton, C.
(2014). Genomic architecture and evolution of clear cell renal carcinomas defined by multiregion sequencing. Nature genetics,
.
show abstract
Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development..
Khattak, M.
Larkin, J.
(2014). Sequential therapy with targeted agents in metastatic renal cell carcinoma: beyond second-line and overcoming drug resistance. World j urol,
Vol.32
(1),
pp. 19-29.
show abstract
Renal cell carcinoma comprises 2-3% of all adult malignancies and its incidence is increasing. Overall survival of patients with advanced disease has increased over the last decade due to the development of many effective targeted agents. Unfortunately, most patients inevitably develop resistance to these agents. While our understanding of the underlying resistance mechanisms has improved, there remain multiple challenges in order to overcome resistance to targeted agents. Sequential and combination therapy with a variety of novel drugs has been evaluated to maintain ongoing clinical benefit and potentially overcome drug resistance. Retrospective data suggest that further anti-angiogenic therapy may be beneficial in advanced renal cell carcinoma after prior progression on two targeted agents with a similar or different mechanism of action. However, further randomised data are needed to better define the role of these agents beyond second-line therapy in the treatment of renal cell carcinoma..
McArthur, G.A.
Chapman, P.B.
Robert, C.
Larkin, J.
Haanen, J.B.
Dummer, R.
Ribas, A.
Hogg, D.
Hamid, O.
Ascierto, P.A.
Garbe, C.
Testori, A.
Maio, M.
Lorigan, P.
Lebbé, C.
Jouary, T.
Schadendorf, D.
O'Day, S.J.
Kirkwood, J.M.
Eggermont, A.M.
Dréno, B.
Sosman, J.A.
Flaherty, K.T.
Yin, M.
Caro, I.
Cheng, S.
Trunzer, K.
Hauschild, A.
(2014). Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet oncol,
Vol.15
(3),
pp. 323-332.
show abstract
BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech..
Hutson, T.E.
Bukowski, R.M.
Rini, B.I.
Gore, M.E.
Larkin, J.M.
Figlin, R.A.
Barrios, C.H.
Escudier, B.
Lin, X.
Fly, K.
Martell, B.
Matczak, E.
Motzer, R.J.
(2014). Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br j cancer,
Vol.110
(5),
pp. 1125-1132.
show abstract
BACKGROUND: We retrospectively analyzed sunitinib outcome as a function of age in metastatic renal cell carcinoma (mRCC) patients. METHODS: Data were pooled from 1059 patients in six trials. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were compared by log-rank test between patients aged <70 (n=857; 81%) and ≥70 (n=202; 19%) years. RESULTS: In first-line patients, median PFS was comparable in younger and older patients, 9.9 vs 11.0 months, respectively (HR, 0.89; 95% CI: 0.73-1.09; P=0.2629), as was median OS, 23.6 vs 25.6 months (HR, 0.93; 95% CI: 0.74-1.18; P=0.5442). Similarly, in cytokine-refractory patients, median PFS was 8.1 vs 8.4 months (HR, 0.79; 95% CI: 0.49-1.28; P=0.3350), while median OS was 20.2 vs 15.8 months (HR, 1.14; 95% CI: 0.73-1.79; P=0.5657). Some treatment-emergent adverse events were significantly less common in younger vs older patients, including fatigue (60% vs 69%), cough (20% vs 29%), peripheral edema (17% vs 27%), anemia (18% vs 25%), decreased appetite (13% vs 29%), and thrombocytopenia (16% vs 25%; all P<0.05). Hand-foot syndrome was more common in younger patients (32% vs 24%). CONCLUSIONS: Advanced age should not be a deterrent to sunitinib therapy and elderly patients may achieve additional clinical benefit..
Martin-Liberal, J.
Lagares-Tena, L.
Larkin, J.
(2014). Prospects for MEK inhibitors for treating cancer. Expert opin drug saf,
Vol.13
(4),
pp. 483-495.
show abstract
INTRODUCTION: The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma). AREAS COVERED: We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years. EXPERT OPINION: MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds..
Larkin, J.
Del Vecchio, M.
Ascierto, P.A.
Krajsova, I.
Schachter, J.
Neyns, B.
Espinosa, E.
Garbe, C.
Sileni, V.C.
Gogas, H.
Miller, W.H.
Mandalà, M.
Hospers, G.A.
Arance, A.
Queirolo, P.
Hauschild, A.
Brown, M.P.
Mitchell, L.
Veronese, L.
Blank, C.U.
(2014). Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet oncol,
Vol.15
(4),
pp. 436-444.
show abstract
BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. METHODS: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. FINDINGS: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). INTERPRETATION: Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. FUNDING: F Hoffmann-La Roche..
Turajlic, S.
Furney, S.J.
Stamp, G.
Rana, S.
Ricken, G.
Oduko, Y.
Saturno, G.
Springer, C.
Hayes, A.
Gore, M.
Larkin, J.
Marais, R.
(2014). Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Ann oncol,
Vol.25
(5),
pp. 959-967.
show abstract
BACKGROUND: BRAF is mutated in ∼42% of human melanomas (COSMIC. http://www.sanger.ac.uk/genetics/CGP/cosmic/) and pharmacological BRAF inhibitors such as vemurafenib and dabrafenib achieve dramatic responses in patients whose tumours harbour BRAF(V600) mutations. Objective responses occur in ∼50% of patients and disease stabilisation in a further ∼30%, but ∼20% of patients present primary or innate resistance and do not respond. Here, we investigated the underlying cause of treatment failure in a patient with BRAF mutant melanoma who presented primary resistance. METHODS: We carried out whole-genome sequencing and single nucleotide polymorphism (SNP) array analysis of five metastatic tumours from the patient. We validated mechanisms of resistance in a cell line derived from the patient's tumour. RESULTS: We observed that the majority of the single-nucleotide variants identified were shared across all tumour sites, but also saw site-specific copy-number alterations in discrete cell populations at different sites. We found that two ubiquitous mutations mediated resistance to BRAF inhibition in these tumours. A mutation in GNAQ sustained mitogen-activated protein kinase (MAPK) signalling, whereas a mutation in PTEN activated the PI3 K/AKT pathway. Inhibition of both pathways synergised to block the growth of the cells. CONCLUSIONS: Our analyses show that the five metastases arose from a common progenitor and acquired additional alterations after disease dissemination. We demonstrate that a distinct combination of mutations mediated primary resistance to BRAF inhibition in this patient. These mutations were present in all five tumours and in a tumour sample taken before BRAF inhibitor treatment was administered. Inhibition of both pathways was required to block tumour cell growth, suggesting that combined targeting of these pathways could have been a valid therapeutic approach for this patient..
Kelderman, S.
Heemskerk, B.
van Tinteren, H.
van den Brom, R.R.
Hospers, G.A.
van den Eertwegh, A.J.
Kapiteijn, E.W.
de Groot, J.W.
Soetekouw, P.
Jansen, R.L.
Fiets, E.
Furness, A.J.
Renn, A.
Krzystanek, M.
Szallasi, Z.
Lorigan, P.
Gore, M.E.
Schumacher, T.N.
Haanen, J.B.
Larkin, J.M.
Blank, C.U.
(2014). Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer immunology immunotherapy,
Vol.63
(5),
pp. 449-458.
Gupta, A.
Love, S.
Schuh, A.
Shanyinde, M.
Larkin, J.M.
Plummer, R.
Nathan, P.D.
Danson, S.
Ottensmeier, C.H.
Lorigan, P.
Collins, L.
Wise, A.
Asher, R.
Lisle, R.
Middleton, M.R.
(2014). DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. Annals of oncology,
Vol.25
(5),
pp. 968-974.
Martin-Liberal, J.
Larkin, J.
(2014). New RAF kinase inhibitors in cancer therapy. Expert opin pharmacother,
Vol.15
(9),
pp. 1235-1245.
show abstract
INTRODUCTION: Alterations in some key components of the MAPK pathway, such as BRAF, have been found to be related to the development of several malignancies. A number of BRAF inhibitors have been developed in recent years. Two of these compounds, vemurafenib and dabrafenib, have been licensed for the treatment of BRAF-mutant advanced melanoma. AREAS COVERED: This article reviews the antitumour activity and safety of the BRAF inhibitors, vemurafenib and dabrafenib. Moreover, early clinical data available for the most promising new members of this family of drugs as well as the novel therapeutic strategy of dual RAF-MEK inhibition is reviewed. A perspective of the potential role of MAPK inhibition in the treatment of cancer in forthcoming years is also provided. EXPERT OPINION: Inhibition of BRAF has achieved highly successful results in patients affected by BRAF-mutated melanoma and has revolutionised their care. Its efficacy in other malignancies is currently under evaluation in monotherapy and as combination with other agents. Early clinical results of concomitant inhibition of BRAF and MEK suggest that this therapeutic approach is superior to either BRAF or MEK inhibition alone. Identification of BRAF mutations sensitive to treatment is essential for the success of these drugs..
Benson, C.
Vitfell-Rasmussen, J.
Maruzzo, M.
Fisher, C.
Tunariu, N.
Mitchell, S.
Al-Muderis, O.
Thway, K.
Larkin, J.
Judson, I.
(2014). A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: the Royal Marsden Hospital experience. Anticancer res,
Vol.34
(7),
pp. 3663-3668.
show abstract
UNLABELLED: Perivascular epithelioid cell tumors (PEComas) are rare tumors driven by tuberous sclerosis complex gene mutations causing up-regulation of mTOR. We report the outcome of ten consecutive patients treated with sirolimus or temsirolimus. PATIENTS AND METHODS: A retrospective analysis was performed on patients seen between 2007 and 2013. Demographic and treatment data were collected and radiological response was assessed. RESULTS: Ten patients were investigated, eight females, with median age of 47.5 years. Nine patients received sirolimus, one temsirolimus. The median treatment duration was 128 (range=7-1,366 days). Temsirolimus was given at 25 mg IV weekly and median starting dose of sirolimus was 3 mg daily. Seven patients were evaluable for response by RECIST: 5 showed partial response (50%), 1 stable disease (10%) and 1 progressive disease (10%). Two patients progressed rapidly on treatment. One patient stopped due to grade 3 hyperlipidaemia although CT scan shows maintained response. Three patients continue on treatment while the remainder stopped due to disease progression. CONCLUSION: Our study confirms that mTOR inhibition with sirolimus/temsirolimus is well-tolerated with good radiological responses, albeit short-lived, and supports its use in PEComas..
Larkin, J.
Fishman, M.
Wood, L.
Negrier, S.
Olivier, K.
Pyle, L.
Gorbunova, V.
Jonasch, E.
Andrews, L.
Staehler, M.
(2014). Axitinib for the treatment of metastatic renal cell carcinoma: recommendations for therapy management to optimize outcomes. Am j clin oncol,
Vol.37
(4),
pp. 397-403.
show abstract
Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment. .
Furney, S.J.
Turajlic, S.
Stamp, G.
Thomas, J.M.
Hayes, A.
Strauss, D.
Gavrielides, M.
Xing, W.
Gore, M.
Larkin, J.
Marais, R.
(2014). The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis. Pigment cell & melanoma research,
Vol.27
(5),
pp. 835-838.
Coupe, N.
Corrie, P.
Hategan, M.
Larkin, J.
Gore, M.E.
Gupta, A.
Wise, A.
Suter, S.
Ciria, C.
Love, S.
Collins, L.
Middleton, M.R.
(2014). A Phase 1, Dose Escalation Study of Paclitaxel with Gsk1120212 (Trametinib) for the Treatment of Advanced Melanoma. Annals of oncology,
Vol.25,
pp. iv379-iv379.
Schadendorf, D.
Amonkar, M.M.
Stroyakovskiy, D.
Levchenko, E.
Gogas, H.
De Braud, F.G.
Grob, J.
Bondarenko, I.
Garbe, C.
Lebbe, C.
Larkin, J.
Chiarion-Sileni, V.
Millward, M.
Arance, A.
Mandalà, M.
Casey, M.
Demarini, D.J.
Irani, J.
Aktan, G.
Long, G.V.
(2014). Combi-D: Quality of Life (Qol) Impact of the Combination of Dabrafenib and Trametinib (D + T) Versus Dabrafenib Monotherapy (D) in Patients with Braf V600E/K Unresectable or Metastatic Melanoma in a Phase III Trial. Annals of oncology,
Vol.25,
pp. iv377-iv377.
Gravis, G.
Chanez, B.
Derosa, L.
Beuselinck, B.
Laguerre, B.
Barthelemy, P.
Brachet, P.E.
Lobbedez, F.J.
Escudier, B.
Stewart, G.D.
Harrison, D.
Laird, A.
Vasudev, N.
Ralph, C.
Larkin, J.
Lote, H.
Walz, J.
Thomassin, J.
Salem, N.
Boher, J.M.
(2014). Impact on Overall Survival of Glandular Metastasis in Patients with Metastatic Clear Cell Renal Cell Carcinoma on Behalf of the Renal Cross Channel Group. Annals of oncology,
Vol.25,
pp. iv286-iv286.
Larkin, J.
Okines, A.
(2014). Precision Medicine in Kidney Cancer and Clinical Trial Designs. Annals of oncology,
Vol.25,
pp. iv17-iv17.
Nobbenhuis, M.A.
Lalondrelle, S.
Larkin, J.
Banerjee, S.
(2014). Management of melanomas of the gynaecological tract. Curr opin oncol,
Vol.26
(5),
pp. 508-513.
show abstract
PURPOSE OF REVIEW: Primary melanomas originating from the gynaecological tract are rare and aggressive cancers. The 5-year survival is around 10%. The majority of tumours differ from cutaneous melanomas, which arise from the skin, by developing from melanocytes located in mucosal epithelium. The clinical behaviour, prognosis and the biology of mucosal melanomas are distinct from cutaneous melanomas. In this article, we summarize the current management of melanomas of the gynaecological tract (vulva, vagina, ovary and cervix) and discuss the progress in developing new treatments. RECENT FINDINGS: The management of mucosal melanomas has not changed substantially over the last decade and the prognosis remains poor. Surgery remains the primary treatment of choice in all localized melanomas of the genital tract. Radiotherapy and chemotherapy are options but have limited success for the majority of women. Activation of c-KIT occurs in vulvar melanomas. Clinical trials of targeted agents are underway. SUMMARY: As a result of the rarity of gynaecological tract melanomas, challenges associated with their anatomical locations and resistance to conventional radiotherapy and chemotherapy, this group of conditions remain difficult to treat and continue to have a poor prognosis. A greater understanding of the molecular profile of these cancers may provide promising targeted approaches..
Pickering, L.
Larkin, J.
(2014). Systemic anti-cancer therapy (SACT) dataset. The lancet oncology,
Vol.15
(10),
pp. 1063-1063.
Leijen, S.
Barlesi, F.
Eberhardt, W.E.
Martinez, G.M.
Dieras, V.
Schellens, J.H.
Middleton, M.
Calvo, E.
Paz-Ares, L.
Larkin, J.
Jodrell, D.
Soria, J.C.
(2014). OCULAR TOXICITIES OBSERVED WITH MEK INHIBITOR RO4987655 (CH4987655) IN A SINGLE AGENT PHASE I STUDY WITH EXTENSION IN PATIENTS WITH ADVANCED SOLID TUMORS. British journal of clinical pharmacology,
Vol.78
(4),
pp. 769-769.
Thian, Y.
Gutzeit, A.
Koh, D.-.
Fisher, R.
Lote, H.
Larkin, J.
Sohaib, A.
(2014). Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic renal cell carcinoma treated with sunitinib. Radiology,
Vol.273
(2),
pp. 452-461.
show abstract
PURPOSE: To compare revised Choi criteria that incorporate concurrent size and attenuation changes at early follow-up imaging with Response Evaluation Criteria in Solid Tumors ( RECIST Response Evaluation Criteria in Solid Tumors ) 1.1 and original Choi criteria in stratification of clinical outcomes in patients with metastatic renal cell carcinoma ( mRCC metastatic renal cell carcinoma ) treated with sunitinib. MATERIALS AND METHODS: Institutional review board approved this retrospective study and waived informed consent. Baseline and first follow-up computed tomographic scans in 69 patients (50 men, 19 women; mean age, 60.3 years; range, 19-83 years) with mRCC metastatic renal cell carcinoma treated with sunitinib from October 1, 2008, to March 1, 2013, were evaluated for tumor response by using RECIST Response Evaluation Criteria in Solid Tumors 1.1, original Choi criteria, and revised Choi criteria. Correlations with overall survival ( OS overall survival ) and progression-free survival ( PFS progression-free survival ) were compared and stratified according to each radiologic criteria with Kaplan-Meier and multivariate Cox regression analysis. RESULTS: Median follow-up time was 29.7 months (95% confidence interval [ CI confidence interval ]: 18.9, 45.9). Response according to revised Choi criteria was independently correlated with OS overall survival (hazard ratio, 0.47 [95% CI confidence interval : 0.23, 0.99]; P = .046) and PFS progression-free survival (hazard ratio, 0.53 [95% CI confidence interval : 0.29, 0.99]; P = .047). Response according to RECIST Response Evaluation Criteria in Solid Tumors was not significantly correlated with OS overall survival (hazard ratio, 0.65 [95% CI confidence interval : 0.27, 1.58]; P = .344) or PFS progression-free survival (hazard ratio, 0.89 [95% CI confidence interval : 0.42, 1.91]; P = .768). Response according to original Choi criteria was not significantly correlated with OS overall survival (hazard ratio, 0.60 [95% CI confidence interval : 0.32, 1.11]; P = .106) or PFS progression-free survival (hazard ratio, 0.59 [95% CI confidence interval : 0.34, 1.02]; P = .060). Median OS overall survival and PFS progression-free survival in responders according to revised Choi criteria was 39.4 months (95% CI confidence interval : 9.1, upper limit not estimated) and 13.7 months (95% CI confidence interval : 6.4, 24.6), respectively, compared with 12.8 months (95% CI confidence interval : 8.7, 18.0) and 5.3 months (95% CI confidence interval : 3.9, 8.4), respectively, in nonresponders. CONCLUSION: Contemporaneous reduction in tumor size and attenuation were correlated with favorable clinical outcomes. Response according to revised Choi criteria showed better correlation with clinical outcomes compared with that according to RECIST Response Evaluation Criteria in Solid Tumors or original Choi criteria in patients with mRCC metastatic renal cell carcinoma treated with sunitinib..
Kenny, L.M.
Tomasi, G.
Turkheimer, F.
Larkin, J.
Gore, M.
Brock, C.S.
Mangar, S.
Aboagye, E.O.
(2014). Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [18F]fluciclatide kinetics and [15O]H2O PET. Ejnmmi research,
Vol.4
(1).
Larkin, J.
Ascierto, P.A.
Dréno, B.
Atkinson, V.
Liszkay, G.
Maio, M.
Mandalà, M.
Demidov, L.
Stroyakovskiy, D.
Thomas, L.
de la Cruz-Merino, L.
Dutriaux, C.
Garbe, C.
Sovak, M.A.
Chang, I.
Choong, N.
Hack, S.P.
McArthur, G.A.
Ribas, A.
(2014). Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N engl j med,
Vol.371
(20),
pp. 1867-1876.
show abstract
BACKGROUND: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)..
Long, G.V.
Stroyakovskiy, D.
Gogas, H.
Levchenko, E.
de Braud, F.
Larkin, J.
Garbe, C.
Jouary, T.
Hauschild, A.
Grob, J.J.
Sileni, V.C.
Lebbe, C.
Mandala, M.
Millward, M.
Arance, A.
Bondarenko, I.
Haanen, J.B.
Hansson, J.
Utikal, J.
Ferraresi, V.
Kovalenko, N.
Mohr, P.
Probachai, V.
Schadendorf, D.
Nathan, P.
Robert, C.
Ribas, A.
DeMarini, D.J.
Irani, J.G.
Casey, M.
Ouellet, D.
Martin, A.-.
Le, N.
Patel, K.
Flaherty, K.
(2014). Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. New england journal of medicine,
Vol.371
(20),
pp. 1877-1888.
Antonia, S.J.
Larkin, J.
Ascierto, P.A.
(2014). Immuno-oncology combinations: a review of clinical experience and future prospects. Clin cancer res,
Vol.20
(24),
pp. 6258-6268.
show abstract
Immuno-oncology is an evolving treatment modality that includes immunotherapies designed to harness the patient's own immune system. This approach is being studied for its potential to improve long-term survival across multiple tumor types. It is now important to determine how immunotherapies may be most effectively used to achieve the best possible patient outcomes. Combining or sequencing immunotherapies that target distinct immune pathways is a logical approach, with the potential to further enhance the magnitude of the antitumor immune response over single agents. Early clinical data in patients with melanoma treated with two immune checkpoint inhibitors, ipilimumab and nivolumab, suggest support for this combination approach. Numerous other combination approaches are being evaluated in early-phase clinical trials; however, their clinical activity remains unknown. Clinical experience to date has shown that when combining an immuno-oncology agent with an existing therapeutic modality, it is important to determine the optimal dose, schedule, and sequence..
Zimmer, L.
Barlesi, F.
Martinez-Garcia, M.
Dieras, V.
Schellens, J.H.
Spano, J.-.
Middleton, M.R.
Calvo, E.
Paz-Ares, L.
Larkin, J.
Pacey, S.
Venturi, M.
Kraeber-Bodéré, F.
Tessier, J.J.
Eberhardt, W.E.
Paques, M.
Guarin, E.
Meresse, V.
Soria, J.-.
(2014). Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin cancer res,
Vol.20
(16),
pp. 4251-4261.
show abstract
PURPOSE: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. EXPERIMENTAL DESIGN: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. RESULTS: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. CONCLUSIONS: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR..
Sanchez-Laorden, B.
Viros, A.
Girotti, M.R.
Pedersen, M.
Saturno, G.
Zambon, A.
Niculescu-Duvaz, D.
Turajlic, S.
Hayes, A.
Gore, M.
Larkin, J.
Lorigan, P.
Cook, M.
Springer, C.
Marais, R.
(2014). BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells By Reactivating MEK and ERK Signaling. Science signaling,
Vol.7
(318).
Fisher, R.
Horswell, S.
Rowan, A.
Salm, M.P.
de Bruin, E.C.
Gulati, S.
McGranahan, N.
Stares, M.
Gerlinger, M.
Varela, I.
Crockford, A.
Favero, F.
Quidville, V.
André, F.
Navas, C.
Grönroos, E.
Nicol, D.
Hazell, S.
Hrouda, D.
O'Brien, T.
Matthews, N.
Phillimore, B.
Begum, S.
Rabinowitz, A.
Biggs, J.
Bates, P.A.
McDonald, N.Q.
Stamp, G.
Spencer-Dene, B.
Hsieh, J.J.
Xu, J.
Pickering, L.
Gore, M.
Larkin, J.
Swanton, C.
(2014). Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome biology,
Vol.15
(8),
p. 433.
show abstract
full text
Background
Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.
Results
We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma.
Conclusions
In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity..
Ascierto, P.A.
Grimaldi, A.M.
Anderson, A.C.
Bifulco, C.
Cochran, A.
Garbe, C.
Eggermont, A.M.
Faries, M.
Ferrone, S.
Gershenwald, J.E.
Gajewski, T.F.
Halaban, R.
Hodi, F.S.
Kefford, R.
Kirkwood, J.M.
Larkin, J.
Leachman, S.
Maio, M.
Marais, R.
Masucci, G.
Melero, I.
Palmieri, G.
Puzanov, I.
Ribas, A.
Saenger, Y.
Schilling, B.
Seliger, B.
Stroncek, D.
Sullivan, R.
Testori, A.
Wang, E.
Ciliberto, G.
Mozzillo, N.
Marincola, F.M.
Thurin, M.
(2014). Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013. Journal of translational medicine,
Vol.12.
Khattak, M.A.
Bakr, F.
Krzystanek, M.
Szallasi, Z.
Gerlinger, M.
Santos, C.
Swanton, C.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2013). Prognostic and predictive markers in metastatic renal cell carcinoma. J clin oncol,
Vol.31
(7),
pp. 971-972.
Sinha, R.
Edmonds, K.
Newton-Bishop, J.
Gore, M.
Larkin, J.
Fearfield, L.
(2013). Erythema Nodosum-Like Panniculitis in Patients With Melanoma Treated With Vemurafenib. Journal of clinical oncology,
Vol.31
(19),
pp. E320-E321.
Larkin, J.
Paine, A.
Tumur, I.
Cappelleri, J.C.
Healey, P.J.
Foley, G.
Mitchell, S.
Kroes, M.
Chen, C.
(2013). Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis. Expert opin pharmacother,
Vol.14
(1),
pp. 27-39.
show abstract
OBJECTIVES: A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib. METHODS: Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI). RESULTS: Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival (PFS), axitinib was superior compared with placebo (HR = 0.25, 95% CrI: 0.17 - 0.38), sorafenib (HR = 0.46, 95% CrI: 0.32 - 0.68) and pazopanib (HR = 0.47, 95% CrI: 0.26 - 0.85). An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib. CONCLUSION: Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy..
Khattak, M.A.
Fisher, R.
Hughes, P.
Gore, M.
Larkin, J.
(2013). Ipilimumab activity in advanced uveal melanoma. Melanoma res,
Vol.23
(1),
pp. 79-81.
show abstract
Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM..
Fisher, R.
Gore, M.
Larkin, J.
(2013). Current and future systemic treatments for renal cell carcinoma. Semin cancer biol,
Vol.23
(1),
pp. 38-45.
show abstract
Systemic treatment of renal cell carcinoma has changed dramatically since 2007, with the development and approval of six new agents, which target complex molecular pathways regulating tumour angiogenesis and cell proliferation and survival. These treatments have significantly improved survival times in metastatic renal cell carcinoma, but remain palliative. A number of newer agents are in clinical development, which offer theoretical advantages over existing treatments, and research methodologies are adapting with the aim of defining an individualised approach to therapy which exploits the underlying tumour biology. This review will provide an overview of current and emerging systemic treatments and how they might be integrated with surgical therapy, with a particular focus on advanced, clear cell metastatic renal cell carcinoma..
Girotti, M.R.
Pedersen, M.
Sanchez-Laorden, B.
Viros, A.
Turajlic, S.
Niculescu-Duvaz, D.
Zambon, A.
Sinclair, J.
Hayes, A.
Gore, M.
Lorigan, P.
Springer, C.
Larkin, J.
Jorgensen, C.
Marais, R.
(2013). Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer discov,
Vol.3
(2),
pp. 158-167.
show abstract
UNLABELLED: We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR-SFK-STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic efficacy in patients with drug-resistant BRAF-mutant melanoma. SIGNIFICANCE: Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF -mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients..
Khattak, M.
Fisher, R.
Turajlic, S.
Larkin, J.
(2013). Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther adv med oncol,
Vol.5
(2),
pp. 105-118.
show abstract
Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important..
Ascierto, P.A.
Grimaldi, A.M.
Acquavella, N.
Borgognoni, L.
Calabro, L.
Cascinelli, N.
Cesano, A.
Del Vecchio, M.
Eggermont, A.M.
Faries, M.
Ferrone, S.
Fox, B.A.
Gajewski, T.F.
Galon, J.
Gnjatic, S.
Gogas, H.
Kashani-Sabet, M.
Kaufman, H.L.
Larkin, J.
Lo, R.S.
Mantovani, A.
Margolin, K.
Melief, C.
McArthur, G.
Palmieri, G.
Puzanov, I.
Ribas, A.
Seliger, B.
Sosman, J.
Suenaert, P.
Tarhini, A.A.
Trinchieri, G.
Vidal-Vanaclocha, F.
Wang, E.
Ciliberto, G.
Mozzillo, N.
Marincola, F.M.
Thurin, M.
(2013). Future perspectives in melanoma research Meeting report from the "Melanoma Bridge Napoli, December 2nd-4th 2012". Journal of translational medicine,
Vol.11.
Fearfield, L.
Newton-Bishop, J.A.
Sinha, R.
Edmonds, K.
Gore, M.E.
Larkin, J.
(2013). Second primary melanomas on treatment with vemurafenib: reply from the authors. Br j dermatol,
Vol.168
(4),
pp. 888-889.
Turajlic, S.
Ali, Z.
Yousaf, N.
Larkin, J.
(2013). Phase I/II RAF kinase inhibitors in cancer therapy. Expert opin investig drugs,
Vol.22
(6),
pp. 739-749.
show abstract
INTRODUCTION: Aberrant activation of RAF signalling is a frequent finding in human cancers. BRAF is the only RAF family member that is commonly mutated, whilst CRAF and ARAF play important roles in the signal transduction from mutant RAS. BRAF-specific inhibitors have been more effective in the treatment of BRAF-mutant melanoma than BRAF-mutant thyroid and colorectal cancers. AREAS COVERED: The review summarises the experience with RAF kinase inhibitors, including efficacy, modes of acquired resistance, and the mechanism behind the progression of pre-malignant RAS-mutant lesions observed with RAF kinase inhibitors. The authors review all the completed and ongoing Phase I or II clinical trials of RAF kinase inhibitors and discuss in detail the rationale behind the combinatorial approaches. EXPERT OPINION: The success of RAF kinase inhibitors has demonstrated the necessity of genotype-driven treatment selection for cancer patients. The spectrum of responses in different tumour types is explained by feedback events that are determined by cell lineage. Dissection of these events and the mechanisms of acquired resistance will determine the appropriate combination therapies. Ongoing characterisation of RAS-MAPK regulation in malignant cells may aid the development of novel agents that have greater potency for the inhibition of activated RAF kinase, and lesser propensity for promotion of RAS-mutant tumours..
Furney, S.J.
Turajlic, S.
Stamp, G.
Nohadani, M.
Carlisle, A.
Thomas, J.M.
Hayes, A.
Strauss, D.
Gore, M.
van den Oord, J.
Larkin, J.
Marais, R.
(2013). Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. J pathol,
Vol.230
(3),
pp. 261-269.
show abstract
Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular, the mutation signatures are not indicative of ultraviolet light- or tobacco smoke-induced DNA damage. Genes previously reported as mutated in other cancers were also mutated in mucosal melanoma. Notably, there were substantially more copy number and structural variations in mucosal melanoma than have been reported in cutaneous melanoma. Thus, mucosal and cutaneous melanomas are distinct diseases with discrete genetic features. Our data suggest that different mechanisms underlie the genesis of these diseases and that structural variations play a more important role in mucosal than in cutaneous melanomagenesis..
Martinez, P.
Birkbak, N.J.
Gerlinger, M.
McGranahan, N.
Burrell, R.A.
Rowan, A.J.
Joshi, T.
Fisher, R.
Larkin, J.
Szallasi, Z.
Swanton, C.
(2013). Parallel evolution of tumour subclones mimics diversity between tumours. J pathol,
Vol.230
(4),
pp. 356-364.
show abstract
Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome..
Fisher, R.
Larkin, J.
(2013). Individualising treatment choices in a crowded treatment algorithm. European journal of cancer supplements,
Vol.11
(2),
pp. 160-168.
Ali, Z.
Yousaf, N.
Larkin, J.
(2013). Melanoma epidemiology, biology and prognosis. European journal of cancer supplements,
Vol.11
(2),
pp. 81-91.
Gerlinger, M.
Quezada, S.A.
Peggs, K.S.
Furness, A.J.
Fisher, R.
Marafioti, T.
Shende, V.H.
McGranahan, N.
Rowan, A.J.
Hazell, S.
Hamm, D.
Robins, H.S.
Pickering, L.
Gore, M.
Nicol, D.L.
Larkin, J.
Swanton, C.
(2013). Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J pathol,
Vol.231
(4),
pp. 424-432.
show abstract
The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and β-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367-16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, -0.218 to 0.465). 3-93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches..
Yousaf, N.
Larkin, J.
(2013). Axitinib in advanced renal-cell carcinoma. Lancet oncol,
Vol.14
(13),
pp. 1245-1246.
Henrion, M.
Frampton, M.
Scelo, G.
Purdue, M.
Ye, Y.
Broderick, P.
Ritchie, A.
Kaplan, R.
Meade, A.
McKay, J.
Johansson, M.
Lathrop, M.
Larkin, J.
Rothman, N.
Wang, Z.
Chow, W.-.
Stevens, V.L.
Ryan Diver, W.
Gapstur, S.M.
Albanes, D.
Virtamo, J.
Wu, X.
Brennan, P.
Chanock, S.
Eisen, T.
Houlston, R.S.
(2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer. Hum mol genet,
Vol.22
(4),
pp. 825-831.
show abstract
Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10(-8); odds ratio 1.29, 95% CI: 1.18-1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC..
Vasudev, N.S.
Goh, V.
Juttla, J.K.
Thompson, V.L.
Larkin, J.M.
Gore, M.
Nathan, P.D.
Reynolds, A.R.
(2013). Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy. British journal of cancer,
Vol.109
(5).
Karapanagiotou, E.M.
Roulstone, V.
Twigger, K.
Ball, M.
Tanay, M.
Nutting, C.
Newbold, K.
Gore, M.E.
Larkin, J.
Syrigos, K.N.
Coffey, M.
Thompson, B.
Mettinger, K.
Vile, R.G.
Pandha, H.S.
Hall, G.D.
Melcher, A.A.
Chester, J.
Harrington, K.J.
(2012). Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies. Clin cancer res,
Vol.18
(7),
pp. 2080-2089.
show abstract
PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment..
Pacey, S.
Gore, M.
Chao, D.
Banerji, U.
Larkin, J.
Sarker, S.
Owen, K.
Asad, Y.
Raynaud, F.
Walton, M.
Judson, I.
Workman, P.
Eisen, T.
(2012). A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest new drugs,
Vol.30
(1),
pp. 341-349.
show abstract
PURPOSE: A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG. PATIENTS AND METHODS: Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity. RESULTS: Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses. CONCLUSION: Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered..
Fisher, R.
Cahalin, P.
Gore, M.
Larkin, J.
(2012). A tale of two tumours and a plea for progress. Lancet oncol,
Vol.13
(2),
pp. 124-125.
Turajlic, S.
Furney, S.J.
Lambros, M.B.
Mitsopoulos, C.
Kozarewa, I.
Geyer, F.C.
Mackay, A.
Hakas, J.
Zvelebil, M.
Lord, C.J.
Ashworth, A.
Thomas, M.
Stamp, G.
Larkin, J.
Reis-Filho, J.S.
Marais, R.
(2012). Whole genome sequencing of matched primary and metastatic acral melanomas. Genome res,
Vol.22
(2),
pp. 196-207.
show abstract
Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion..
Gruenwald, V.
Karakiewicz, P.I.
Bavbek, S.E.
Miller, K.
Machiels, J.-.
Lee, S.-.
Larkin, J.
Bono, P.
Rha, S.Y.
Castellano, D.
Blank, C.U.
Knox, J.J.
Hawkins, R.
Anak, O.
Rosamilia, M.
Booth, J.
Pirotta, N.
Bodrogi, I.
Grp, R.E.
(2012). An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. European journal of cancer,
Vol.48
(3),
pp. 324-332.
Fisher, R.
Larkin, J.
(2012). Treatment of brain metastases in patients with melanoma. Lancet oncol,
Vol.13
(5),
pp. 434-435.
Young, K.
Minchom, A.
Larkin, J.
(2012). BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future oncol,
Vol.8
(5),
pp. 499-507.
show abstract
Following Phase I and II studies revealing vemurafenib to be a safe potent inhibitor of mutated BRAF in patients with metastatic melanoma, a multicenter randomized Phase III trial was carried out to compare vemurafenib with dacarbazine in treatment-naive patients. The interim analysis results from this trial, BRIM-3, were sufficient for an independent data and safety monitoring board to recommend crossover from dacarbazine to vemurafenib, vemurafenib being associated with a relative risk reduction of 63% in the risk of death and 74% in the risk of death or disease progression compared with dacarbazine (p < 0.001 for both comparisons) with an acceptable toxicity profile. Such striking results have prompted analysis of our approach to the classification and treatment of metastatic melanoma in an age of molecular markers and targeted therapy..
Gerlinger, M.
Santos, C.R.
Spencer-Dene, B.
Martinez, P.
Endesfelder, D.
Burrell, R.A.
Vetter, M.
Jiang, M.
Saunders, R.E.
Kelly, G.
Dykema, K.
Rioux-Leclercq, N.
Stamp, G.
Patard, J.J.
Larkin, J.
Howell, M.
Swanton, C.
(2012). Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target. J pathol,
Vol.227
(2),
pp. 146-156.
show abstract
Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta-analysis of five ccRCC expression datasets. MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intra-tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse-free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC..
Larkin, J.
Esser, N.
Calvo, E.
Tsuchihashi, Z.
Fiedler, U.
Graeser, R.
Kim, D.
(2012). Efficacy of sequential treatment with sunitinib-everolimus in an orthotopic mouse model of renal cell carcinoma. Anticancer res,
Vol.32
(7),
pp. 2399-2406.
show abstract
BACKGROUND/AIM: Sequential treatment with targeted agents is standard of care for patients with metastatic renal cell carcinoma (mRCC). However, clinical data directly comparing treatment outcomes with a mammalian target of rapamycin inhibitor or a vascular endothelial growth factor-targeted agent in the second-line setting are lacking. We evaluated sequential treatment in a syngeneic, orthotopic mouse model of mRCC. MATERIALS AND METHODS: BALB/c mice were orthotopically implanted with murine RCC (RENCA) cells expressing luciferase and randomized to vehicle, sunitinib, sunitinib followed by sorafenib, or sunitinib followed by everolimus. Tumor growth and metastases were assessed by in vivo (whole body) and ex vivo (primary tumor, lung, liver) luciferase activity and necropsies, performed on day 20 or 46 for vehicle and treatment groups, respectively. RESULTS: Sunitinib followed by everolimus was associated with reduced luciferase activity and primary tumor weight and volume compared with sunitinib, and sunitinib followed by sorafenib. CONCLUSION: Sequential therapy with sunitinib followed by everolimus demonstrated significant antitumor and anti-metastatic effects..
Gerlinger, M.
Rowan, A.J.
Horswell, S.
Math, M.
Larkin, J.
Endesfelder, D.
Gronroos, E.
Martinez, P.
Matthews, N.
Stewart, A.
Tarpey, P.
Varela, I.
Phillimore, B.
Begum, S.
McDonald, N.Q.
Butler, A.
Jones, D.
Raine, K.
Latimer, C.
Santos, C.R.
Nohadani, M.
Eklund, A.C.
Spencer-Dene, B.
Clark, G.
Pickering, L.
Stamp, G.
Gore, M.
Szallasi, Z.
Downward, J.
Futreal, P.A.
Swanton, C.
(2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N engl j med,
Vol.366
(10),
pp. 883-892.
show abstract
BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)..
Khattak, M.
Gore, M.
Larkin, J.
Strauss, D.
Thomas, M.
Hayes, A.
Harrington, K.
(2012). Adjuvant nodal irradiation in melanoma. Lancet oncol,
Vol.13
(8),
pp. e326-e327.
Larkin, J.M.
Fisher, R.A.
Gore, M.E.
(2012). Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review. Clinical oncology,
Vol.24
(6),
pp. 410-412.
Thway, K.
du Parcq, J.
Larkin, J.M.
Fisher, C.
Livni, N.
(2012). Metastatic renal mucinous tubular and spindle cell carcinoma Atypical behavior of a rare, morphologically bland tumor. Ann diagn pathol,
Vol.16
(5),
pp. 407-410.
show abstract
Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, distinctive renal neoplasm characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, typically with low-grade nuclei and a myxoid or mucinous background. It is characteristically of low malignant potential, and only rare metastatic cases have been reported. We describe a case in which the patient presented with extensive regional and distant metastases, but both primary and metastatic tumor showed the typical histomorphology of bland cuboidal or spindle cells lacking pleomorphism, mitoses, and necrosis. Almost all previous cases of metastatic MTSCCs have shown nuclear atypia or sarcomatoid morphology of the primary tumor; and metastatic renal MTSCC in which the primary neoplasm does not display atypical features is exceptional, serving to highlight that these rare tumors can behave aggressively even with "indolent" histological appearances..
Larkin, J.M.
Blank, C.U.
Bono, P.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Grünwald, V.
REACT Study Group,
(2012). Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy. J clin oncol,
Vol.30
(5_suppl),
p. 391.
show abstract
391 Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval. METHODS: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE. RESULTS: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.) Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population. [Table: see text]..
Blank, C.U.
Bono, P.
Larkin, J.M.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Grünwald, V.
REACT Study Group,
(2012). Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. J clin oncol,
Vol.30
(5_suppl),
p. 402.
show abstract
402 Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval. METHODS: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed. RESULTS: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9-49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1-83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease. CONCLUSIONS: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients..
Larkin, J.M.
Blank, C.U.
Bono, P.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Gruenwald, V.
Grp, R.E.
(2012). Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy. Journal of clinical oncology,
Vol.30
(5).
Blank, C.U.
Bono, P.
Larkin, J.M.
Gogov, S.
Panneerselvam, A.
Garay, C.A.
Gruenwald, V.
Grp, R.E.
(2012). Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. Journal of clinical oncology,
Vol.30
(5).
Khattak, M.A.
Fisher, R.A.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2012). Endobronchial metastases from renal cell carcinoma: a late manifestation of the disease with an increasing incidence. Bju int,
Vol.110
(10),
pp. 1407-1408.
Sinha, R.
Edmonds, K.
Newton-Bishop, J.A.
Gore, M.E.
Larkin, J.
Fearfield, L.
(2012). Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br j dermatol,
Vol.167
(5),
pp. 987-994.
show abstract
Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma..
Proskorovsky, I.
Benedict, A.
Larkin, J.M.
Sandin, R.
Chen, C.
(2012). AXITINIB (AXI) AND BEST SUPPORTIVE CARE (BSC) IN THE TREATMENT OF SUNITINIB-REFRACTORY PATIENTS WITH METASTATIC RENAL CELL CARCINOMA (MRCC): RESULTS OF A SIMULATED TREATMENT COMPARISON (STC) ANALYSES. Value in health,
Vol.15
(7),
pp. A410-A410.
Flaherty, K.T.
Robert, C.
Hersey, P.
Nathan, P.
Garbe, C.
Milhem, M.
Demidov, L.V.
Hassel, J.C.
Rutkowski, P.
Mohr, P.
Dummer, R.
Trefzer, U.
Larkin, J.M.
Utikal, J.
Dreno, B.
Nyakas, M.
Middleton, M.R.
Becker, J.C.
Casey, M.
Sherman, L.J.
Wu, F.S.
Ouellet, D.
Martin, A.-.
Patel, K.
Schadendorf, D.
Grp, M.E.
(2012). Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. New england journal of medicine,
Vol.367
(2),
pp. 107-114.
Gerlinger, M.
Rowan, A.
Horswell, S.
Larkin, J.
Endesfelder, D.
Gronroos, E.
Martinez, P.
Matthews, N.
Stewart, A.
Tarpey, P.
Varela, I.
Phillimore, B.
Begum, S.
McDonald, N.
Butler, A.
Jones, D.
Raine, K.
Latimer, C.
Santos, C.
Nohadani, M.
Eklund, A.
Spencer-Dene, B.
Clark, G.
Pickering, L.
Stamp, G.
Gore, M.
Szallasi, Z.
Downward, J.
Futreal, P.A.
Swanton, C.
(2012). Abstract 964: Intra-tumor heterogeneity and Darwinian selection revealed by multi-region exome sequencing of renal cell carcinomas. Clinical research,
.
Kirkwood, J.M.
Bastholt, L.
Robert, C.
Sosman, J.
Larkin, J.
Hersey, P.
Middleton, M.
Cantarini, M.
Zazulina, V.
Kemsley, K.
Dummer, R.
(2012). Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma. Clinical cancer research,
Vol.18
(2),
pp. 555-567.
Larkin, J.
Goh, X.Y.
Vetter, M.
Pickering, L.
Swanton, C.
(2012). Epigenetic regulation in RCC: opportunities for therapeutic intervention?. Nat rev urol,
Vol.9
(3),
pp. 147-155.
show abstract
Renal cell carcinoma (RCC) is a constellation of malignancies of different histological subtypes arising from the renal parenchyma. The clear cell histological subtype (ccRCC) accounts for around 75% of RCCs and is characterized by distinct genetic abnormalities, of which the loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is the most common. Inactivation of other tumor suppressor genes such as SETD2, KDM6A, KDM5C and PBRM1 has been reported in ccRCC--notably, the proteins encoded by these genes are involved in histone and chromatin regulation. Furthermore, the PBRM1 and SETD2 genes are located on the short arm of chromosome 3 near the VHL locus. Chromatin and histones modify gene expression and, as a consequence, their function is tightly regulated. Data from RNA interference (RNAi) assays suggest that loss of function of PBRM1 drives proliferation and growth of ccRCC, but the clinical relevance of this is unclear and restoring the function of these genes for therapeutic purposes is likely to be challenging. An improved understanding of histone and chromatin regulation in RCC biology and the consequences of intratumor heterogeneity might identify novel targets in RCC and present alternative therapeutic opportunities..
Swanton, C.
Larkin, J.
Gerlinger, M.
(2012). Intratumor Heterogeneity and Branched Evolution REPLY. New england journal of medicine,
Vol.366
(22),
pp. 2133-2133.
Fisher, R.
Pender, A.
Thillai, K.
Chowdhury, S.
Pickering, L.
Khabra, K.
Gore, M.
Larkin, J.
(2012). Observation as a treatment strategy for advanced renal cell carcinoma-a call for prospective validation. Front oncol,
Vol.2,
p. 155.
Fisher, R.
Larkin, J.
(2012). Vemurafenib: a new treatment for BRAF-V600 mutated advanced melanoma. Cancer manag res,
Vol.4,
pp. 243-252.
show abstract
The BRAF inhibitor, vemurafenib, has demonstrated improved progression-free and overall survival compared with chemotherapy in a randomized trial, and represents a new standard of care in patients with advanced melanoma harboring a BRAF-V600 mutation. A BRAF-V600 mutation is identified in approximately half of patients with cutaneous melanoma, and is unequivocally a biomarker predictive of profound clinical benefit for these patients. However, acquired vemurafenib resistance is a major clinical challenge and therapy is not yet curative. A substantial body of translational research has been performed alongside clinical trials of vemurafenib, providing key insights into the molecular basis of response and resistance. This review summarizes the development of vemurafenib for the treatment of BRAF-V600 mutant melanoma and discusses how knowledge of critical signaling pathways will be applied for its optimal clinical use in future..
Fisher, R.
Larkin, J.
Swanton, C.
(2012). Inter and intratumour heterogeneity: a barrier to individualized medical therapy in renal cell carcinoma?. Front oncol,
Vol.2,
p. 49.
Suwaki, N.
Vanhecke, E.
Atkins, K.M.
Graf, M.
Swabey, K.
Huang, P.
Schraml, P.
Moch, H.
Cassidy, A.M.
Brewer, D.
Al-Lazikani, B.
Workman, P.
De-Bono, J.
Kaye, S.B.
Larkin, J.
Gore, M.E.
Sawyers, C.L.
Nelson, P.
Beer, T.M.
Geng, H.
Gao, L.
Qian, D.Z.
Alumkal, J.J.
Thomas, G.
Thomas, G.V.
(2011). A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Sci transl med,
Vol.3
(85),
p. 85ra47.
show abstract
Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. Although therapies targeted to the molecules vascular endothelial growth factor and mammalian target of rapamycin have shown clinical effectiveness, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens and determined that Src kinase signaling is elevated in RCC cells that retain wild-type von Hippel-Lindau (VHL) protein expression. RCC cell lines and xenografts with wild-type VHL exhibited sensitivity to the Src inhibitor dasatinib, in contrast to cell lines that lacked the VHL protein, which were resistant. Forced expression of hypoxia-inducible factor (HIF) in RCC cells with wild-type VHL diminished Src signaling output by repressing transcription of the Src activator protein tyrosine phosphatase 1B (PTP1B), conferring resistance to dasatinib. Our results suggest that a HIF-regulated VHL-PTP1B-Src signaling pathway determines the sensitivity of RCC to Src inhibitors and that stratification of RCC patients with antibody-based profiling may identify patients likely to respond to Src inhibitors in RCC clinical trials..
Gore, M.E.
Larkin, J.M.
(2011). Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies. British journal of cancer,
Vol.104
(3),
pp. 399-406.
Khan, O.A.
Gore, M.
Lorigan, P.
Stone, J.
Greystoke, A.
Burke, W.
Carmichael, J.
Watson, A.J.
McGown, G.
Thorncroft, M.
Margison, G.P.
Califano, R.
Larkin, J.
Wellman, S.
Middleton, M.R.
(2011). A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. British journal of cancer,
Vol.104
(5),
pp. 750-755.
Okera, M.
Chan, S.
Dernede, U.
Larkin, J.
Popat, S.
Gilbert, D.
Jones, L.
Osuji, N.
Sykes, H.
Oakley, C.
Pickering, L.
Lofts, F.
Chowdhury, S.
(2011). A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network Interpretation of study results in light of NCAG/NCEPOD findings. British journal of cancer,
Vol.104
(3),
pp. 407-412.
Larkin, J.
Swanton, C.
Pickering, L.
(2011). Optimizing treatment of metastatic renal cell carcinoma by changing mechanism of action. Expert rev anticancer ther,
Vol.11
(4),
pp. 639-649.
show abstract
Novel targeted agents, such as VEGF receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and mTOR inhibitors, have improved therapy for metastatic renal cell carcinoma. Sequential administration of agents with similar mechanisms of action has shown some efficacy in small retrospective studies; however, prospective Phase II studies have reached differing conclusions, and there is a current lack of prospective randomized data to validate this approach. Sequential administration of agents with different mechanisms of action has shown clinical efficacy in prospective trials, including a randomized Phase III study (RECORD-1) of the mTOR inhibitor everolimus, the only targeted agent recommended for use after VEGFR-TKI failure in metastatic renal cell carcinoma. Ongoing research will further define the relative merits of other sequences in terms of clinical outcome..
Bex, A.
Larkin, J.
Blank, C.
(2011). Non-Clear Cell Renal Cell Carcinoma: How New Biological Insight May Lead to New Therapeutic Modalities. Current oncology reports,
Vol.13
(3),
pp. 240-248.
Fisher, R.
Pickering, L.
Larkin, J.
(2011). New targeted therapies for renal cell carcinoma. Expert opin investig drugs,
Vol.20
(7),
pp. 933-945.
show abstract
INTRODUCTION: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease. AREAS COVERED: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010. EXPERT OPINION: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers..
Josephs, D.
Hutson, T.E.
Cowey, C.L.
Pickering, L.M.
Larkin, J.M.
Gore, M.E.
Van Hemelrijck, M.
McDermott, D.F.
Powles, T.
Chowdhury, P.
Karapetis, C.
Harper, P.G.
Choueiri, T.K.
Chowdhury, S.
(2011). Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or on haemodialysis. Bju international,
Vol.108
(8),
pp. 1279-1283.
Larkin, J.M.
Gore, M.E.
(2011). Primary Excision Margins and Sentinel Lymph Node Biopsy in Clinically Node-negative Melanoma of the Trunk or Extremities. Clinical oncology,
Vol.23
(9),
pp. 569-571.
Minchom, A.
Young, K.
Larkin, J.
(2011). Ipilimumab: showing survival benefit in metastatic melanoma. Future oncol,
Vol.7
(11),
pp. 1255-1264.
show abstract
Ipilimumab is a fully humanized monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4. Data from preclinical and clinical studies have shown that ipilimumab can cause tumor regression in patients with metastatic melanoma with response rates of 5.8-22%. Phase III trials have demonstrated a benefit in median overall survival in the first-line setting in combination with dacarbazine versus dacarbazine alone (11.2 vs 9.1 months) and in the second-line setting in combination with gp100 versus gp100 alone (10.1 vs 6.4 months). The main toxicities of ipilimumab are immune related, most commonly skin and gastrointestinal. Bowel perforation and treatment-related deaths have occurred, although prompt use of steroids and other immunosuppressive agents can minimize this risk..
Sanz-Moreno, V.
Gaggioli, C.
Yeo, M.
Albrengues, J.
Wallberg, F.
Viros, A.
Hooper, S.
Mitter, R.
Féral, C.C.
Cook, M.
Larkin, J.
Marais, R.
Meneguzzi, G.
Sahai, E.
Marshall, C.J.
(2011). ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer cell,
Vol.20
(2),
pp. 229-245.
show abstract
Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network..
Larkin, J.M.
Fisher, R.A.
Pickering, L.M.
Sohaib, S.A.
Ghosn, M.
Christmas, T.
Cordiner, R.L.
Gore, M.E.
(2011). Chromophobe Renal Cell Carcinoma With Prolonged Response to Sequential Sunitinib and Everolimus. Journal of clinical oncology,
Vol.29
(9),
pp. E241-E242.
Ratnayake, G.
Pender, A.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2011). Intrapatient correlation of clinical benefit from VEGF and mTOR inhibition in metastatic renal cell carcinoma. Journal of clinical oncology,
Vol.29
(15).
Hutson, T.E.
Bukowski, R.M.
Rini, B.I.
Gore, M.E.
Larkin, J.M.
Figlin, R.A.
Barrios, C.H.
Escudier, B.
Lin, X.
Fly, K.D.
Martell, B.
Matczak, E.
Motzer, R.J.
(2011). A pooled analysis of the efficacy and safety of sunitinib in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). Journal of clinical oncology,
Vol.29
(15).
Leary, A.
Pickering, L.M.
Larkin, J.M.
Leach, M.O.
Gore, M.E.
Sohaib, A.
Collins, D.J.
Koh, D.
(2011). Quantitative diffusion-weighted (DW) MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response of renal cell carcinoma (RCC) to treatment with sunitinib. Journal of clinical oncology,
Vol.29
(15).
Fisher, R.A.
Pender, A.
Thillai, K.
Chowdhury, S.
Pickering, L.M.
Rose, S.S.
Gore, M.E.
Larkin, J.M.
(2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. Journal of clinical oncology,
Vol.29
(15).
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with (V600E)BRAF-mutated melanoma. J clin oncol,
Vol.29
(18_suppl),
p. LBA4.
show abstract
LBA4 Background: About 50% of melanomas have an activating (V600E)BRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in (V600E)BRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with (V600E)BRAF mutation. METHODS: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for (V600E)BRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m(2), IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. RESULTS: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. CONCLUSIONS: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, (V600E)BRAF-mutated metastatic melanoma..
Hutson, T.E.
Bukowski, R.M.
Rini, B.I.
Gore, M.E.
Larkin, J.M.
Figlin, R.A.
Barrios, C.H.
Escudier, B.
Lin, X.
Fly, K.D.
Martell, B.
Matczak, E.
Motzer, R.J.
(2011). A pooled analysis of the efficacy and safety of sunitinib in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). J clin oncol,
Vol.29
(15_suppl),
p. 4604.
show abstract
4604 Background: Sunitinib is approved multinationally for mRCC treatment (Tx), with demonstrated activity and tolerability in both the first- and second-line Tx settings. Here, we report a retrospective analysis of the efficacy and safety of sunitinib as a function of age in pts with mRCC from 6 clinical trials. METHODS: Analyses included pooled data from 1,059 pts who received single-agent sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the first- (n=783; 74%) and second-line (n=276; 26%) Tx settings. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared between pts <70 vs. ≥70 yrs of age by log-rank test. Adverse event (AE) rates were also compared. RESULTS: Of 1,059 pts, 857 (81%) were of age <70 yrs and 202 (19%) ≥70 yrs, with median ages of 57 and 73 yrs, respectively. 73% and 59% were male, but otherwise baseline characteristics were similar. Median PFS was similar in both groups (9.0 vs. 10.9 mo; HR, 0.85; 95% CI, 0.70-1.02; P=0.0830), as was median OS (23.3 vs. 23.7 mo; HR, 0.94; 95% CI, 0.76-1.15; P=0.5441). In addition, efficacy was similar by age regardless of Tx setting. In first-line pts <70 vs. ≥70 yrs, median PFS and OS were 9.9 mo (95% CI, 8.3-10.7) vs. 11.0 mo (95% CI, 9.0-14.7) and 23.5 mo (95% CI, 21.1-27.6) vs. 25.5 mo (95% CI, 21.6-38.4); in second-line pts, median PFS and OS were 8.1 mo (95% CI, 7.8-8.7) vs. 8.4 mo (95% CI, 6.3-14.2) and 20.1 mo (95% CI, 16.2-25.0) vs. 15.8 mo (95% CI, 13.7-23.9). Most Tx-emergent AEs occurred at similar rates in both age groups; however, some AEs were significantly less common in pts aged <70 vs. ≥70 yrs, including fatigue (59% vs. 69%), decreased appetite/weight (29% vs. 53%), cough (20% vs. 29%), peripheral edema (17% vs. 27%), anemia (17% vs. 25%), and thrombocytopenia (16% vs. 25%; all P<0.05). Hand-foot syndrome was more common in younger pts (32% vs. 24%; P<0.05). CONCLUSIONS: In pts with mRCC, the efficacy of sunitinib was comparable in the elderly population, deriving similar benefit as younger pts regardless of Tx setting. The AE profiles were also similar, although some AEs were more common in elderly pts..
Fisher, R.A.
Pender, A.
Thillai, K.
Chowdhury, S.
Pickering, L.M.
St Rose, S.
Gore, M.E.
Larkin, J.M.
(2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. J clin oncol,
Vol.29
(15_suppl),
p. 4630.
show abstract
4630 Background: Patients with metastatic renal cell carcinoma (mRCC) are heterogenous, with significant variation in clinical course. The use of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) kinase inhibitors has dramatically changed the prognosis for these patients. However, these treatments are non-curative, necessitating chronic therapy. There is a cohort of patients with indolent disease in whom the initiation of systemic therapy is often deferred. It is inferred that the planned deferment of systemic therapy does not negatively impact on clinical benefit, but there is a lack of published data in the 'kinase inhibitor era' to support this contention. METHODS: This was a retrospective study. Patients with mRCC treated with sunitinib who had a planned period of observation prior to the initiation of systemic therapy because of asymptomatic or slowly progressive disease were analysed. The primary objective was to determine the progression free survival (PFS) of patients on deferred first-line systemic therapy. RESULTS: Records of 251 patients treated with sunitinib between 2005 and 2010 were reviewed; 64 patients who met the criteria were identified. The median age at diagnosis was 56 years and 75% were male; 80% had clear cell mRCC. All patients but one had a favourable or intermediate prognosis (Heng). The median time from diagnosis of metastases to starting treatment was 14.7 months (95% CI 10.4-16.3) Initial systemic therapy was interferon for 28% of patients and sunitinib for 65% of patients. Interferon patients had a median PFS of 6.3 months (95% CI 3.3-9.9), and sunitinib patients had a median PFS of 4.3 months (95% CI 3.6-7.3). Patients who received a VEGFR kinase inhibitor as second-line therapy after interferon had a median PFS of 7 months (95% CI 4.3-12.5). The median overall survival for all patients was 35 months (95% CI 26-42.3). CONCLUSIONS: In this cohort of patients with indolent favourable or intermediate prognosis mRCC, systemic treatment was deferred by a median of over one year but the efficacy of delayed sunitinib treatment was less than expected. Further study is required to define the group of patients for whom delayed systemic therapy is optimal..
Larkin, J.M.
Turajlic, S.
Nathan, P.D.
Lorigan, P.
Stamp, G.
Gonzalez de Castro, D.
Martin, N.
Griffiths, J.
Edmonds, K.
Sarker, S.
James, M.G.
A'Hern, R.
Coombes, G.
Snowdon, C.
Bliss, J.M.
Gore, M.E.
Marais, R.
(2011). A phase II trial of nilotinib in the treatment of patients with KIT mutated advanced acral and mucosal melanoma (NICAM). J clin oncol,
Vol.29
(15_suppl),
p. TPS229.
show abstract
TPS229 Background: Recent studies have indicated that KIT mutations occur in approximately 20% of acral and mucosal melanomas (Curtin, al. 2006; Beadling, et al. 2008). Several case reports have shown that KIT mutated melanomas can respond to treatment with KIT inhibitors (Hodi et al. 2008; Lutzky et al. 2008; Quintas-Cardama et al. 2008; Handolias et al. 2010; Itoh, et al. 2010; Satzger et al. 2010; Terheyden et al. 2010; Woodman and Davies 2010) suggesting that such tumours critically depend on upregulated KIT signalling. Nilotinib, which potently inhibits the tyrosine kinase activity of BCR-ABL and KIT, has been evaluated in patients with advanced KIT mutated GIST and has shown clinical efficacy at well tolerated doses (Demetri et al. 2009; Montemurro et al. 2009; Schlemmer et al. 2010). METHODS: NICAM is a single arm 2-stage open label phase II study of nilotinib in KIT mutated advanced mucosal or acral melanoma. Patients with KIT mutations known to confer resistance to nilotinib are excluded. The primary objective in this feasibility study is to evaluate the efficacy of nilotinib in KIT mutated advanced mucosal and acral melanoma with a primary endpoint of progression free survival at 6 months. Secondary endpoints include response rate at 12 weeks; overall survival; toxicity of treatment; correlation between the response to nilotinib and KIT genotype, KIT gene copy number and KIT expression. In addition, the following will be explored: 1. Suppression of phosphorylation of KIT and downstream pathways on day 15 tumour biopsies; 2. Possible mechanisms of resistance by analysis of biopsies obtained at disease progression; 3. The use of circulating tumour DNA for non-invasive KIT mutational testing; 4. Genetic lesions that potentially cooperate with oncogenic KIT in melanoma (using Next Generation Sequencing). All patients are treated until disease progression or unacceptable toxicity. If 2 or more of the first 9 patients are progression free at 6 months, patient entry will continue into the second stage until a total of 24 patients have been recruited. To date, 45 patients have been registered and screened for KIT mutation and 5 patients have entered the study..
Leary, A.
Pickering, L.M.
Larkin, J.M.
Leach, M.O.
Gore, M.E.
Sohaib, A.
Collins, D.J.
Koh, D.
(2011). Quantitative diffusion-weighted (DW) MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response of renal cell carcinoma (RCC) to treatment with sunitinib. J clin oncol,
Vol.29
(15_suppl),
p. TPS154.
show abstract
TPS154 Background: The anti-angiogenic tyrosine kinase inhibitor, sunitinib has been shown to significantly improve progression-free (PFS) and overall survival in RCC (Motzer 2009). However assessing response by conventional imaging is inadequate as sunitinib can alter perfusion and induce necrosis with no change in tumor size (Jaffe 2006). DW-MRI measures the motion of water molecules using the apparent diffusion coefficient (ADC) to quantify tissue diffusivity (D), an indirect measure of tissue density. ADC values are low in viable tumor and increase with treatment-induced apoptosis or necrosis (Theony 2010). In addition, DW-MRI obtained using low diffusion weightings can measure tissue perfusion (f) (Theony 2010; Koh 2006). Therefore DW-MRI may provide an early marker of response to sunitinib in RCC by detecting both changes in perfusion (anti-angiogenic effect) and changes in tissue diffusivity (necrosis). METHODS: This is a single arm prospective study. Main inclusion criteria are metastatic clear cell RCC, eligible for first-line sunitinib and target lesion >2.5cm assessable by functional MRI. 30 patients will be enrolled and undergo DW-MRI at baseline and after 7 and 28 days of sunitinib. Two baseline DW-MRI are performed 1 day apart to assess reproducibility. Objective response will be assessed on CT after 12 weeks by RECIST and pts followed up for PFS. The primary endpoint is to determine whether DW-MRI can identify responders versus non-responders to sunitinib in RCC. Secondary endpoints include investigating whether quantitative measurement of diffusion and perfusion (ADC, D, f) by DW-MRI correlates with objective tumor response and PFS. For DW-MRI, targeted acquisition measurements will be made using up to 10b-values, ranging between 0 and 1000s/mm(2). Unenhanced T1- and T2-, DCE-MR imaging sequences will also be performed. Paired baseline measurements will be used to compute measurement reproducibility. Absolute and % change in ADC, D and f at 7 and 28 days will be compared to baseline, and the limits of baseline reproducibility (Bland-Altman Statistics) used to define whether biomarker change is significant..
Ratnayake, G.
Pender, A.
Pickering, L.M.
Gore, M.E.
Larkin, J.M.
(2011). Intrapatient correlation of clinical benefit from VEGF and mTOR inhibition in metastatic renal cell carcinoma. J clin oncol,
Vol.29
(15_suppl),
p. e15175.
show abstract
e15175 Background: Sequential inhibition of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signalling is the standard systemic therapy paradigm for metastatic renal cell carcinoma (mRCC). We investigated whether clinical benefit for mRCC patients treated with VEGF inhibitors (VEGFi) predicted clinical benefit from mTOR inhibitors (mTORi) in individual patients. METHODS: Data were analysed for mRCC patients treated with VEGFi and mTORi in either sequence. Median time on treatment (TT) for VEGFi and mTORi were compared using the Mann-Whitney U test, and Kendall's tau to assess correlation of VEGFi and mTORi TT for each patient. For patients treated with >1 VEGFi, TT for the 1(st) VEGFi was analysed. Patients were divided into 4 groups: TT of mTORi and VEGFi <6 and >6 months duration, comparing duration between groups with a log rank test. Modified Motzer Scores (mMS) at time of 1(st) VEGFi/mTORi for these 4 groups were calculated as surrogate markers for tumour biology. RESULTS: Thirty five patients received both mTORi and VEGFi to disease progression, of whom only 2 received mTORi before VEGFi. Seven patients were female, and median age at start of 1(st) VEGFi/mTORi was 58.9 years. The median TT for VEGFi and mTORi were 5.4 months (95% CI 2.2-8.6) and 6.9 months (95% CI 2.5-11.3) respectively, and not significantly different. Kendall tau intrapatient correlation coefficient for TT on mTORi and VEGFi was 0.069 (p=0.56), suggesting no significant correlation. The mean mMS for patients with TT on mTORi <6 vs >6 months were 2.00 and 1.89 (median 2 and 2) respectively (p=0.79), and 2.11 and 1.18 (median 2 and 1) respectively (p=0.00092) for TT on VEGFi. CONCLUSIONS: In this small retrospective analysis, there was no significant correlation within patients between TT for mTORi and VEGFi. The significantly lower mMS for patients on VEGFi with a TT >6 months vs <6 months is consistent with previous analyses by Heng and colleagues. No such significant difference was seen with mTORi, implying mMS may not have the same prognostic value. These associations require further study..
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas. J clin oncol,
Vol.29
(15_suppl),
p. LBA4.
show abstract
LBA4 The full, final text of this abstract will be available in Part II of the 2011 Annual Meeting Proceedings, distributed onsite at the Meeting on June 4, 2011, and as a supplement to the June 20, 2011, issue of Journal of Clinical Oncology..
Grünwald, V.
Karakiewicz, P.I.
Bavbek, S.E.
Miller, K.
Machiels, J.H.
Lee, S.
Larkin, J.M.
Bono, P.
Rha, S.Y.
Castellano, D.E.
Blank, C.U.
Knox, J.J.
Hawkins, R.
Yuan, R.R.
Rosamilia, M.
Booth, J.L.
Bodrogi, I.
REACT Study Group,
(2011). Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. J clin oncol,
Vol.29
(15_suppl),
p. 4601.
show abstract
4601 Background: The phase III RECORD-1 trial established everolimus as the only agent proven to benefit patients with metastatic renal cell carcinoma (mRCC) after failure of initial VEGFr-TKI therapy. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, more than doubled median progression-free survival compared with placebo, from 1.9 months to 4.9 months. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated in order to address an unmet medical need and provide everolimus in advance of regulatory approval and commercial availability to patients with mRCC after failure of initial VEGFr-TKI therapy. METHODS: REACT was an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ). Eligible patients had measurable or nonmeasurable mRCC of any histology, were intolerant of, or progressed while on, VEGFr-TKI therapy, had a Karnofsky performance score ≥70%, and had adequate bone marrow, hepatic, and renal function. Patients received everolimus 10 mg/day orally, with dose and schedule modifications allowed for toxicity. The primary objective of REACT was to evaluate the long-term safety of everolimus in patients with mRCC, as determined by the overall incidence of grade 3/4 and serious adverse events (AEs). Tumor response to everolimus was also assessed according to RECIST. RESULTS: A total of 1367 patients from 34 countries were enrolled. Safety findings and tumor responses were consistent with those observed in RECORD-1. The most commonly reported grade 3/4 AEs were anemia (13.4%), fatigue (6.7%), and dyspnea (6.4%), and the most frequent serious AEs were dyspnea (5.0%), pneumonia (4.7%), and anemia (4.1%). Median dose intensity was 10.0 mg/day; relative dose intensity ranged from 0.90 to 1.10 in 68.9% of patients. CONCLUSIONS: REACT evaluated the safety and tolerability of everolimus in a broader patient population than the controlled trial RECORD-1. Everolimus was well tolerated, with no new safety issues identified and infrequent dose reductions/interruptions in the majority of patients..
Gruenwald, V.
Karakiewicz, P.I.
Bavbek, S.E.
Miller, K.
Machiels, J.H.
Lee, S.
Larkin, J.M.
Bono, P.
Rha, S.Y.
Castellano, D.E.
Blank, C.U.
Knox, J.J.
Hawkins, R.
Yuan, R.R.
Rosamilia, M.
Booth, J.L.
Bodrogi, I.
Grp, R.E.
(2011). Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. Journal of clinical oncology,
Vol.29
(15).
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas. Journal of clinical oncology,
Vol.29
(15).
Chapman, P.B.
Hauschild, A.
Robert, C.
Larkin, J.M.
Haanen, J.B.
Ribas, A.
Hogg, D.
O'Day, S.
Ascierto, P.A.
Testori, A.
Lorigan, P.
Dummer, R.
Sosman, J.A.
Garbe, C.
Lee, R.J.
Nolop, K.B.
Nelson, B.
Hou, J.
Flaherty, K.T.
McArthur, G.A.
(2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with (V600E)BRAF-mutated melanoma. Journal of clinical oncology,
Vol.29
(18).
Chapman, P.B.
Hauschild, A.
Robert, C.
Haanen, J.B.
Ascierto, P.
Larkin, J.
Dummer, R.
Garbe, C.
Testori, A.
Maio, M.
Hogg, D.
Lorigan, P.
Lebbe, C.
Jouary, T.
Schadendorf, D.
Ribas, A.
O'Day, S.J.
Sosman, J.A.
Kirkwood, J.M.
Eggermont, A.M.
Dreno, B.
Nolop, K.
Li, J.
Nelson, B.
Hou, J.
Lee, R.J.
Flaherty, K.T.
McArthur, G.A.
Grp, B.S.
(2011). Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. New england journal of medicine,
Vol.364
(26),
pp. 2507-2516.
Fisher, R.
Larkin, J.
(2011). Renal cell cancer: what can we learn from pre-operative studies?. Front oncol,
Vol.1,
p. 51.
Larkin, J.
Fisher, R.
Pickering, L.
Thway, K.
Livni, N.
Fisher, C.
Gore, M.
(2010). Metastatic Mucinous Tubular and Spindle Cell Carcinoma of the Kidney Responding to Sunitinib. Journal of clinical oncology,
Vol.28
(28),
pp. E539-2.
Rennalls, L.P.
Seidl, T.
Larkin, J.M.
Wellbrock, C.
Gore, M.E.
Eisen, T.
Bruno, L.
(2010). The melanocortin receptor agonist NDP-MSH impairs the allostimulatory function of dendritic cells. Immunology,
Vol.129
(4),
pp. 610-619.
Mukherji, D.
Larkin, J.
Pickering, L.
(2010). Sunitinib for metastatic renal cell carcinoma. Future oncology,
Vol.6
(9),
pp. 1377-1385.
Goldstein, R.
Pickering, L.
Larkin, J.
(2010). Does axitinib (AG-01376) have a future role in metastatic renal cell carcinoma and other malignancies?. Expert review of anticancer therapy,
Vol.10
(10),
pp. 1545-1557.
Larkin, J.M.
Ferguson, T.R.
Pickering, L.M.
Edmonds, K.
James, M.G.
Thomas, K.
Banerji, U.
Berns, B.
de Boer, C.
Gore, M.E.
(2010). A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma. Br j cancer,
Vol.103
(8),
pp. 1149-1153.
show abstract
BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC..
Pickering, L.M.
Constantinidou, A.
Larkin, J.M.
Sohaib, S.A.
Khatri, P.
Nathan, P.D.
Vinayan, A.
Ferguson, T.
St Rose, S.
Gore, M.E.
(2010). Sunitinib treatment for longer than 2 years for renal cell carcinoma. Journal of clinical oncology,
Vol.28
(15).
Larkin, J.M.
Hess, V.
Pickering, L.M.
Ferguson, T.
Forrest, R.
Gore, M.E.
(2010). Symptomatic brain metastases from renal cell carcinoma during treatment with sunitinib or sorafenib. Journal of clinical oncology,
Vol.28
(15).
Swanton, C.
Juul, N.
Larkin, J.M.
Eklund, A.
Li, Q.
Desmedt, C.
Sotiriou, C.
Pusztal, L.
Szallasi, Z.
(2010). Use of an RNA interference screen-derived mitotic and ceramide pathway metagene to predict response to paclitaxel combination chemotherapy in primary breast cancer. Journal of clinical oncology,
Vol.28
(15).
Larkin, J.
Gore, M.
(2010). Is advanced renal cell carcinoma becoming a chronic disease?. Lancet,
Vol.376
(9741),
pp. 574-575.
Fisher, R.A.
Larkin, J.
(2010). Malignant melanoma (metastatic). Bmj clin evid,
Vol.2010.
show abstract
INTRODUCTION: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6 to 9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide..
Larkin, J.M.
Pyle, L.M.
Gore, M.E.
(2010). Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies. Oncologist,
Vol.15
(11),
pp. 1135-1146.
show abstract
Fatigue is one of the most common symptoms associated with cancer. Persistent fatigue can impair multiple aspects of daily functioning and quality of life, and patients report that treatment-related fatigue has a greater impact than other symptoms, including pain, nausea, and depression. Thus, management of fatigue is recognized as an important component of care for patients with cancer. Treatment of advanced and metastatic renal cell carcinoma (RCC) was, until recently, limited to cytokine-based therapies, which are associated with modest response rates and significant toxicity, including high rates of treatment-related fatigue. The paradigm for RCC treatment has shifted dramatically in the last 5 years with the advent of efficacious targeted therapies. These agents provide the promise of better tolerability because of their more selective mechanisms of action. However, there is considerable variation in the selectivity of targeted agents for RCC, and a review of randomized clinical trials in patients with advanced and/or metastatic disease reveals that there is considerable variation in the tolerability of these agents. Fatigue remains a prominent toxicity with current targeted therapies. Future agents that show better selectivity and potency than current targeted therapies should help to provide better efficacy and tolerability..
Swanton, C.
Larkin, J.M.
Gerlinger, M.
Eklund, A.C.
Howell, M.
Stamp, G.
Downward, J.
Gore, M.
Futreal, P.A.
Escudier, B.
Andre, F.
Albiges, L.
Beuselinck, B.
Oudard, S.
Hoffmann, J.
Gyorffy, B.
Torrance, C.J.
Boehme, K.A.
Volkmer, H.
Toschi, L.
Nicke, B.
Beck, M.
Szallasi, Z.
(2010). Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets. Genome medicine,
Vol.2.
Pickering, L.M.
Pyle, L.
Larkin, J.M.
(2009). Sunitinib is superior to interferon alpha with respect to quality of life for patients with renal cell carcinoma. Nat clin pract oncol,
Vol.6
(1),
pp. 6-7.
show abstract
Randomized trials have shown that both anti-vascular endothelial growth factor (VEGF) therapy and inhibition of the mammalian target of rapamycin have superior clinical efficacy when compared with interferon alpha in the first-line treatment of advanced renal cell carcinoma. In 2007, a pivotal phase III trial randomly allocated 750 patients with advanced renal cell carcinoma to receive either the VEGF-receptor tyrosine kinase inhibitor sunitinib or interferon alpha, and showed that sunitinib led to improved response rates, progression-free and overall survival. In this Practice Point, we discuss the data reported by Cella et al., which showed that the quality of life of patients in this trial was better with sunitinib than interferon alpha; these differences were predominantly due to better control of disease-related symptoms by sunitinib. This landmark study is the first to report comparative quality-of-life data for an anti-VEGF therapy and a cytokine therapy..
Larkin, J.M.
Clarke, R.E.
Pickering, L.M.
(2009). Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: biology and pathways. Medical oncology,
Vol.26,
pp. 40-45.
Larkin, J.M.
Kipps, E.L.
Powell, C.J.
Swanton, C.
(2009). Systemic therapy for advanced renal cell carcinoma. Ther adv med oncol,
Vol.1
(1),
pp. 15-27.
show abstract
Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease..
Sternberg, C.N.
Bellmunt, J.
Gruenwald, V.
Larkin, J.
Mulders, P.
(2009). Advances in the Management of Metastatic Renal Cell Cancer. European urology supplements,
Vol.8
(9),
pp. 758-761.
Larkin, J.
Gore, M.
(2009). HEALTH POLICY The UK 'postcode lottery' in renal cell carcinoma. Nature reviews urology,
Vol.6
(12),
pp. 636-638.
Miller, R.E.
Larkin, J.M.
(2009). Combination systemic therapy for advanced renal cell carcinoma. Oncologist,
Vol.14
(12),
pp. 1218-1224.
show abstract
Outcomes for patients with advanced renal cell carcinoma (RCC) have improved significantly in recent years with the development of novel noncytotoxic systemic therapies. The multitargeted kinase inhibitors sunitinib and sorafenib have been approved for the treatment of advanced RCC, and bevacizumab, a monoclonal anti-vascular endothelial growth factor antibody, has shown significant clinical activity, both as a single agent and in combination with interferon-alpha. The mammalian target of rapamycin inhibitors temsirolimus and everolimus have led to longer overall survival times in poor-risk patients in the first-line setting and longer progression-free survival times in kinase inhibitor refractory patients in the second-line setting, respectively. Despite these advances, almost all patients develop resistance to treatment and cure is rarely seen. There is therefore a need to overcome resistance, induce longer lasting remissions, and improve survival. A potential approach to this is to combine active agents, and the clinical data for combination therapy with novel targeted agents in advanced RCC are reviewed here..
Josephs, D.H.
Hutson, T.E.
Pickering, L.M.
Larkin, J.M.
Choueiri, T.K.
Patel, T.V.
Mcdermott, D.F.
Powles, T.
Harper, P.G.
Chowdhury, S.
(2009). Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma (mRCC) with severe renal impairment or on haemodialysis. J clin oncol,
Vol.27
(15_suppl),
p. 5109.
show abstract
5109 Background: Sunitinib is currently a standard of care for the treatment of mRCC. Due to the inclusion criteria of clinical trials, no studies of sunitinib have enrolled patients with severe renal impairment or those undergoing haemodialysis, and thus further investigation of the effect of sunitinib in this population is required. METHODS: Clinical databases were used to identify all patients with mRCC treated with sunitinib in five institutions internationally. Medical records were searched to identify only those patients with a creatinine clearance (CLcr) of <30ml/min or who had end stage renal disease (ESRD) requiring haemodialysis. Baseline characteristics, toxicity data and progression free survival (PFS) were collected. RESULTS: 21 patients met inclusion criteria with 9 (43%) undergoing haemodialysis. Baseline characteristics include a median age of 62 years (range 44-80); 90% of patients had ECOG PS of 0 or 1; 38% of patients had > 2 metastatic sites and 86% had prior nephrectomy. The estimated median PFS of this cohort was 38 weeks (range 2-120) although progression has not yet been reached in 8 (38%) patients. PR or SD was observed as best response in 17 (81%) patients. The most common treatment-related adverse events (AEs) included fatigue, diarrhoea, hand foot skin reaction (HFSR), nausea and vomiting and rash. Grade 3 treatment related AEs including fatigue, HFSR, diarrhoea and rash occurred in a total of 7 (33%) of patients. Only one patient experienced grade IV toxicity (HFSR). CONCLUSIONS: These data suggest that patients treated with sunitinib who have severe renal impairment, or ESRD on haemodialysis, have a PFS that is comparable to patients with normal renal function. In addition sunitinib appears to be reasonably well tolerated in this group of patients. These preliminary results warrant confirmation in a larger cohort of patients. [Table: see text]..
Carden, C.P.
Myerson, J.S.
Popat, S.
Montes, A.
Larkin, J.M.
Benson, M.J.
O'Brien, M.E.
(2008). Good vibrations and the power of positron thinking: positron emission tomography and endoscopic ultrasound in staging of mesothelioma-two case reports. J thorac oncol,
Vol.3
(5),
pp. 539-541.
Carden, C.P.
Larkin, J.M.
Rosenthal, M.A.
(2008). What is the risk of intracranial bleeding during anti-VEGF therapy?. Neuro oncol,
Vol.10
(4),
pp. 624-630.
show abstract
Vascular endothelial growth factor (VEGF) is a key mediator of physiological and pathological angiogenesis. All solid tumors are dependent on pathological angiogenesis, and anti-VEGF therapy has demonstrated clinical benefit in breast, colorectal, non-small-cell lung, and renal carcinomas. Central nervous system metastases are common in many of these tumor types. An increased risk of bleeding has been reported with anti-VEGF therapy, but the risk of intracranial bleeding is unknown with this type of therapy. We reviewed the available data to investigate the risk of intracranial bleeding with anti-VEGF therapy in the presence and absence of CNS metastases. The PubMed and Medline databases and the Proceedings of the American Society of Clinical Oncology (ASCO) annual meetings were searched for articles, abstracts, and presentations of clinical trials. We identified 57 trials examining the safety and efficacy of anti-VEGF therapy in a total of 10,598 patients. Four trials examined the use of anti-VEGF therapy in treating patients with brain metastases. The presence of CNS metastases was a stated exclusion criterion in 76% of trials. The rate of intracranial bleeding was negligible. We conclude that there is no trial evidence that anti-VEGF therapy confers an increased risk of intracranial bleeding, even in the presence of CNS metastases. Future trials of anti-VEGF therapy should not exclude patients with controlled CNS metastases at enrollment..
Chowdhury, S.
Larkin, J.M.
Gore, M.E.
(2008). Recent advances in the treatment of renal cell carcinoma and the role of targeted therapies. European journal of cancer,
Vol.44
(15),
pp. 2152-2161.
Dernedde, U.
Chan, S.
Sykes, H.
Oakley, C.
Larkin, J.
Popat, S.
Gilbert, D.
Jones, L.
Chowdhury, S.
(2008). South West London Cancer Network (SWLCN) audit of patients with chemotherapy-induced febrile neutropenia (CIFN). Journal of clinical oncology,
Vol.26
(15).
Larkin, J.
Gore, M.
(2008). Malignant melanoma (metastatic). Bmj clin evid,
Vol.2008.
show abstract
INTRODUCTION: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide..
Fearfield, L.A.
Larkin, J.M.
Rowe, A.
A'Hern, R.
Fisher, C.
Francis, N.
MacKie, R.
McCann, B.
Gore, M.E.
Bunker, C.B.
(2007). Expression of p16, CD95, CD95L and Helix pomatia agglutinin in relapsing and nonrelapsing very thin melanoma. British journal of dermatology,
Vol.156
(3),
pp. 440-8.
Larkin, J.M.
Porter, C.D.
(2007). Complement insufficiency limits efficacy in a xenograft model of hyperacute rejection for cancer therapy. Cancer immunology immunotherapy,
Vol.56
(1),
pp. 60-69.
Larkin, J.M.
(2007). Patupilone Antimitotic drug, microtubule-stabilizing agent, oncolytic. Drugs of the future,
Vol.32
(4),
pp. 323-336.
Larkin, J.M.
Kaye, S.B.
(2007). Potential clinical applications of epothilones: a review of phase II studies. Ann oncol,
Vol.18 Suppl 5,
pp. v28-v34.
show abstract
BACKGROUND: Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment. DESIGN: This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design. RESULTS: Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin. CONCLUSIONS: The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens..
Larkin, J.M.
Chowdhury, S.
Gore, M.E.
(2007). Drug insight: advances in renal cell carcinoma and the role of targeted therapies. Nat clin pract oncol,
Vol.4
(8),
pp. 470-479.
show abstract
In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit..
Larkin, J.M.
Hughes, S.A.
Beirne, D.A.
Patel, P.M.
Gibbens, I.M.
Bate, S.C.
Thomas, K.
Eisen, T.G.
Gore, M.E.
(2007). A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. British journal of cancer,
Vol.96
(1),
pp. 44-48.
Larkin, J.M.
Kaye, S.B.
(2006). Epothilones in the treatment of cancer. Expert opinion on investigational drugs,
Vol.15
(6),
pp. 691-12.
Larkin, J.M.
Norsworth, P.J.
A'Hern, R.P.
Eisen, T.G.
Gore, M.E.
Porter, C.D.
(2006). Anti-alpha Gal-dependent complement-mediated cytotoxicity in metastatic melanoma. Melanoma research,
Vol.16
(2),
pp. 157-7.
Larkin, J.M.
Eisen, T.
(2006). Renal cell carcinoma and the use of sorafenib. Ther clin risk manag,
Vol.2
(1),
pp. 87-98.
show abstract
Immunotherapy results in a small overall survival advantage in metastatic renal cell carcinoma (RCC), but there is a need to develop more effective systemic therapies. Angiogenesis has an important role in the pathophysiology of RCC and vascular endothelial growth factor (VEGF) is a key mediator of this process. Sorafenib (BAY 43-9006) is a new agent belonging to a class of drugs called kinase inhibitors and inhibits the VEGF, platelet-derived growth factor (PDGF), and c-KIT receptor tyrosine kinases, amongst others. Sorafenib has shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients pretreated with immunotherapy, whilst prolonged progression-free survival in comparison with placebo in a phase 3 study has been reported. Further phase 3 trials in advanced disease are ongoing and a trial of adjuvant sorafenib therapy in RCC is planned..
Larkin, J.M.
Eisen, T.
(2006). Kinase inhibitors in the treatment of renal cell carcinoma. Crit rev oncol hematol,
Vol.60
(3),
pp. 216-226.
show abstract
Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation..
Larkin, J.M.
Porter, C.D.
(2005). Mice are unsuitable for modelling ABO discordance despite strain-specific A cross-reactive natural IgM. British journal of haematology,
Vol.130
(2),
pp. 310-317.
Larkin, J.M.
Gore, M.E.
(2005). The MRC randomised-controlled trial of interferon-alpha, interleukin-2 and 5-fluorouracil vs interferon-alpha alone in patients with advanced renal cell carcinoma (RE04): Rationale and progress. Clinical oncology,
Vol.17
(5),
pp. 319-321.
Kolomainen, D.F.
Larkin, J.M.
Badran, M.
A'Hern, R.P.
King, D.M.
Fisher, C.
Bridges, J.E.
Blake, P.R.
Barton, D.P.
Shepherd, J.H.
Kaye, S.B.
Gore, M.E.
(2002). Epithelial ovarian cancer metastasizing to the brain: a late manifestation of the disease with an increasing incidence. J clin oncol,
Vol.20
(4),
pp. 982-986.
show abstract
PURPOSE: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site. PATIENTS AND METHODS: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases. RESULTS: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P <.001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P <.001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time. CONCLUSION: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing..
Gulati, S.
Martinez, P.
Joshi, T.
Birbak, N.J.
Santos, C.R.
Rowan, A.J.
Pickering, L.
Gore, M.
Larkin, J.
Szallasi, Z.
Bates, P.A.
Swanton, C.
Gerlinger, M.
Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers. European urology,
.
show abstract
Background: Candidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated.
Objective: To validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising markers to guide biomarker optimisation.
Design, setting, and participants: Cancer-specific survival (CSS) for each of 28 identified genetic or transcriptomic biomarkers was assessed in 350 ccRCC patients. ITH was interrogated in a multiregion biopsy data set of 10 ccRCCs.
Outcome measurements and statistical analysis: Biomarker association with CSS was analysed by univariate and multivariate analyses.
Results and limitations: A total of 17 of 28 biomarkers (TP53 mutations; amplifications of chromosomes 8q, 12, 20q11.21q13.32, and 20 and deletions of 4p, 9p, 9p21.3p24.1, and 22q; low EDNRB and TSPAN7 expression and six gene expression signatures) were validated as predictors of poor CSS in univariate analysis. Tumour stage and the ccB expression signature were the only independent predictors in multivariate analysis. ITH of the ccB signature was identified in 8 of 10 tumours. Several genetic alterations that were significant in univariate analysis were enriched, and chromosomal instability indices were increased in samples expressing the ccB signature. The study may be underpowered to validate low-prevalence biomarkers.
Conclusions: The ccB signature was the only independent prognostic biomarker. Enrichment of multiple poor prognosis genetic alterations in ccB samples indicated that several events may be required to establish this aggressive phenotype, catalysed in some tumours by chromosomal instability. Multiregion assessment may improve the precision of this biomarker..
Henrion, M.Y.
Purdue, M.P.
Scelo, G.
Broderick, P.
Frampton, M.
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